Hydrogel production device and hydrogel production method

Abstract

Provided is a hydrogel production device with which it is possible to suppress the mixing of impurities during the period from the formation of a hydrogel to the time when the hydrogel is used. A hydrogel production device (100) is provided with: a first flow path (212) through which a hydrogel precursor flows; a second flow path (222) through which a gelling agent for gelling the hydrogel precursor flows; a first confluence point (216) of the first flow path (212) and the second flow path (222); a storage container (400) for storing a hydrogel formed by the contact between the hydrogel precursor and the gelling agent; and a hydrogel flow path (300) that hermetically connects at least the storage container (400) and the first confluence point (216).

Description

Technical Field

[0001] This invention relates to a hydrogel manufacturing apparatus and a hydrogel manufacturing method. Background Technology

[0002] Patent Document 1 discloses a method for manufacturing hollow hydrogel fibers made of alginate polymer. In the method described in Patent Document 1, a hydrogel precursor flows along the fluid around the core, and a gelling agent flows around the hydrogel precursor. As a result, the hydrogel precursor gels, thereby forming a fibrous, elongated hydrogel.

[0003] Existing technical documents

[0004] Patent documents

[0005] Patent Document 1: International Publication No. 2011 / 046105 Summary of the Invention

[0006] In Patent Document 1, the hydrogel is formed within a container suitable for hydrogel formation. The formed hydrogel is typically transferred to another suitable container for use when the hydrogel is to be used. Therefore, during the transfer of the hydrogel, it is possible for impurities to be introduced into the hydrogel or the solution containing the hydrogel.

[0007] Therefore, it is desirable to have a hydrogel manufacturing apparatus and a hydrogel manufacturing method that can suppress the introduction of impurities from the formation of the hydrogel to its use.

[0008] An apparatus for manufacturing a hydrogel in one manner includes: a first flow path for supplying a hydrogel precursor; a second flow path for supplying a gelling agent for gelling the hydrogel precursor; a first confluence point of the first flow path and the second flow path; a receiving container for receiving a hydrogel formed by contact between the hydrogel precursor and the gelling agent; and a hydrogel flow path that at least provides closed communication between the receiving container and the first confluence point.

[0009] One method for manufacturing hydrogels uses the aforementioned hydrogel manufacturing apparatus and includes the following steps: flowing a hydrogel precursor into a first flow path; flowing a gelling agent into a second flow path; merging the hydrogel precursor and the gelling agent at a first confluence point to form a hydrogel; and introducing the formed hydrogel into the receiving container through the hydrogel flow path. Attached Figure Description

[0010] Figure 1 This is a schematic diagram of the hydrogel manufacturing apparatus in the first embodiment.

[0011] Figure 2 This is a schematic diagram illustrating the flow path structure of the hydrogel manufacturing apparatus in the first embodiment.

[0012] Figure 3 This is a block diagram of the hydrogel manufacturing apparatus in the first embodiment.

[0013] Figure 4 This is a perspective view showing an example of the structure of the hydrogel formed in the first embodiment.

[0014] Figure 5 yes Figure 4 The cross-sectional view of the hydrogel shown.

[0015] Figure 6 This is a diagram illustrating an example of the data stored in the storage unit in the first embodiment.

[0016] Figure 7 This is a diagram illustrating the status of each import path in the initial stage of leak detection.

[0017] Figure 8 This is an explanation of what follows. Figure 7 A diagram illustrating the status of each import path during the stages.

[0018] Figure 9 This is an explanation of what follows. Figure 8 A diagram illustrating the status of each import path during the stages.

[0019] Figure 10 This is a schematic diagram illustrating the status of each inlet path during the pre-liquid delivery stage.

[0020] Figure 11 This is a schematic diagram illustrating the state of each introductory path during the preparation phase of the pulsation suppression unit and / or debubbling unit.

[0021] Figure 12 This is an explanation of what follows. Figure 11 A diagram illustrating the status of each import path during the stages.

[0022] Figure 13 This is a schematic diagram illustrating the state of each pathway in the stages of hydrogel formation.

[0023] Figure 14 This is a schematic diagram illustrating the structure of the flow path of the hydrogel manufacturing apparatus in the second embodiment.

[0024] Figure 15 This is a block diagram of the hydrogel manufacturing apparatus in the second embodiment.

[0025] Figure 16 This is a perspective view showing an example of the structure of the hydrogel formed in the second embodiment.

[0026] Figure 17 yes Figure 16The cross-sectional view of the hydrogel shown.

[0027] Figure 18 This is a diagram illustrating an example of the data stored in the storage unit in the second embodiment. Detailed Implementation

[0028] The embodiments will now be described with reference to the accompanying drawings. In the following drawings, the same or similar parts are labeled with the same or similar reference numerals. However, it should be noted that the drawings are schematic, and the proportions of dimensions may sometimes differ from reality.

[0029] [First Implementation Method]

[0030] Figure 1 This is a schematic diagram of the hydrogel manufacturing apparatus in the first embodiment. Figure 2 This is a schematic diagram illustrating the flow path structure of the hydrogel manufacturing apparatus in the first embodiment. Figure 3 This is a block diagram of the hydrogel manufacturing apparatus in the first embodiment. It should be noted that... Figure 1 The structure of the flow path is simplified or not shown. The hydrogel manufacturing apparatus 100 may have a first storage section 102, a second storage section 104, a third storage section 106, and flow path components 200.

[0031] The first storage section 102 stores the first fluid. The first fluid is a hydrogel precursor (hereinafter the same). The hydrogel precursor is preferably a solution (containing a sol) containing alginate or agarose. More specifically, the first fluid may be a solution containing sodium alginate, potassium alginate, and ammonium alginate, or a combination thereof. In addition, alginate may be a natural extract or a chemically modified substance. Examples of chemically modified alginate include methacrylated alginate. Alternatively, the first fluid may be a mixture of the aforementioned alginate with agar, agarose, polyethylene glycol (PEG), polylactic acid (PLA), or nanocellulose. In addition to the hydrogel precursor, the first fluid may also contain excipients and / or thickeners.

[0032] The second storage section 104 stores a second fluid (gelling agent) that gels the first fluid (hydrogel precursor) through contact with the first fluid. In the case where the first fluid is the aforementioned alginate polymer material, the second fluid can be a solution containing polyvalent cations. Examples of such solutions include calcium chloride or barium chloride solutions containing calcium or barium ions. The alginate polymer material forms an alginate gel through polyvalent cation crosslinking. In addition to the gelling agent, the second fluid may also contain excipients and / or thickeners.

[0033] The third storage section 106 stores a third fluid. The third fluid can be a sol, gel, or liquid (including suspension). Preferably, the third fluid can be a gel or liquid. The type of gel or liquid constituting the third fluid is not particularly limited. These gels or liquids can be, for example, alginate solutions, chitosan gels, collagen gels, gelatin, peptide gels, fibroin gels, laminin gels, nanocellulose, pullulan, dextran, and culture media, or mixtures thereof. The third fluid may also contain excipients and / or thickeners.

[0034] The hydrogel manufacturing apparatus 100 may include a second actuation unit 107 that moves the fluid within the third storage section 106. In the case that the fluid in the third storage section 106 contains suspended particles, the second actuation unit 107 may be, for example, a stirrer for stirring the third fluid within the third storage section 106, a shaking unit for shaking the third storage section 106 itself, or the like.

[0035] When the third fluid contains, for example, suspended particles, the suspended particles in the third fluid within the third storage section 106 are uniformly dispersed by the action of the second actuation unit 107. Thus, when the hydrogel is formed as described later, the suspended particles are uniformly contained within the hydrogel.

[0036] The flow path component 200 is a component that includes a flow path for the flow of a first fluid, a second fluid, and a third fluid. The flow path component 200 is preferably made of a non-flexible component. For example, the flow path component 200 may be made of a metal or synthetic resin component.

[0037] The flow path component 200 may have a first inlet 210, a second inlet 220, a third inlet 230, and an outlet 240. The first inlet 210 is an inlet for a first fluid and is in fluid communication with the first storage unit 102. The second inlet 220 is an inlet for a second fluid and is in fluid communication with the second storage unit 104. The third inlet 230 is an inlet for a third fluid and is in fluid communication with the third storage unit 106.

[0038] The flow path component 200 may have a first flow path 212, a second flow path 222, and a third flow path 232. The first flow path 212, the second flow path 222, and the third flow path 232 may be formed in the flow path component 200.

[0039] The first flow path 212 is a flow path for the hydrogel precursor to flow, which can be defined by a flow path from the first inlet 210 via the first confluence point 216 (described later) to the outlet 240. In this embodiment, the first flow path 212 extends from the first inlet 210 via the second confluence point 226 (described later) and the first confluence point 216 to the outlet 240. The first fluid flows from the first inlet 210 to the outlet 240 via the first flow path 212.

[0040] The second flow path 222 can be defined by a flow path from the second inlet 220 to the first confluence point 216. The second flow path 222 is the flow path through which the gelling agent flows. The first confluence point 216 is the confluence point of the first flow path 212 and the second flow path 222. The second fluid is introduced from the second inlet 220 through the second flow path 222 and the first confluence point 216 into the first flow path 212, and then reaches the outlet 240.

[0041] The third flow path 232 can be defined by a flow path from the third inlet 230 to the second confluence point 226. The second confluence point 226 is the confluence point of the first flow path 212 and the third flow path 232. The second confluence point 226 can be located upstream of the first confluence point 216 in the flow direction of the first flow path 212. That is, the third flow path 232 is configured to merge with the first flow path 212 at the second confluence point 226, which is upstream of the first confluence point 216. The third fluid is introduced into the first flow path 212 from the third inlet 230 via the third flow path 232, the second confluence point 226, and the first confluence point 216, and then reaches the outlet 240.

[0042] The second flow path 222 is configured such that the second fluid (gelling agent) merges with the first fluid in the first flow path 212 at the first confluence point 216. Thus, the second fluid flows around the flow of the first fluid in the direction of its flow. That is, the second fluid surrounds the first fluid (hydrogel precursor) in a cross-section orthogonal to the flow of the first fluid.

[0043] The first fluid (hydrogel precursor) and the second fluid (gelling agent) come into contact at the first confluence point 216, thereby forming a hydrogel. The hydrogel flows downstream from the first confluence point 216 toward the outlet 240.

[0044] Preferably, the first fluid and the second fluid flow as laminar flows in the first flow path 212 and the second flow path 222, respectively. Thus, the second fluid hardly mixes with the first fluid and regularly surrounds the first fluid in a cross-section orthogonal to the flow direction of the first fluid. Therefore, a hydrogel with a regular shape is easily formed.

[0045] In the first embodiment, the first flow path 212 is configured such that the first fluid merges with the third fluid flowing into the first flow path 212 around the second confluence point 226. Thus, the first fluid flows around the flow of the third fluid along the flow direction of the third fluid. That is, the first fluid surrounds the third fluid in a cross-section orthogonal to the flow direction of the third fluid. In other words, the first fluid flows while maintaining a tube shape surrounding the third fluid, and then contacts the second fluid at the first confluence point 216 to form a hydrogel. Thus, a hydrogel with a tube shape can be formed.

[0046] Preferably, the first fluid and the third fluid flow as laminar flows in the first flow path 212 and the third flow path 232, respectively. Thus, the first fluid hardly mixes with the third fluid in the cross-section orthogonal to the flow of the third fluid, but rather regularly surrounds the third fluid. Therefore, it is easy to form a tubular hydrogel with a regular shape (see also...). Figure 4 ).

[0047] As described above, the flow path component 200 is preferably made of a non-flexible component. In this case, since the first flow path 212, the second flow path 222, and the third flow path 232 are difficult to deform relative to external forces, laminar flow composed of the first fluid, the second fluid, and / or the third fluid can be stably formed within the first flow path 212, the second flow path 222, and the third flow path 232, respectively. Therefore, it is easier to manufacture hydrogels with a more uniform tube shape.

[0048] The diameters of the first flow path 212, the second flow path 222, and the third flow path 232 can be appropriately designed according to the dimensions of each part of the manufactured hydrogel. To form elongated or small hydrogels, the diameters of the first flow path 212, the second flow path 222, and the third flow path 232 can be small. For example, the inner diameter of the first flow path 212, the second flow path 222, and the third flow path 232 can be 5 mm or less, or 3 mm or less. Furthermore, the inner diameter of the outlet 240 can be, for example, 30 mm or less, 10 mm or less, 5 mm or less, or 3 mm or less.

[0049] The distance from the first confluence point 216 to the outlet 240 can be, for example, in the range of 3 mm to 150 mm, preferably in the range of 5 mm to 100 mm, and more preferably in the range of 10 mm to 50 mm. When the distance from the first confluence point 216 to the outlet 240 is long, the hydrogel flows out from the outlet 240 after the shape of the hydrogel in the flow path forming component 200 has stabilized. Therefore, it is possible to suppress the breakage of the hydrogel in the hydrogel flow path 300. In addition, the shorter the distance from the first confluence point 216 to the outlet 240, the smaller the size of the flow path forming component 200 can be.

[0050] The hydrogel manufacturing apparatus 100 may include a frame 120 and a support portion 140 for supporting the flow path forming member 200. The support portion 140 is provided in the frame 120 and fixes the flow path forming member 200 to the frame 120. As a result, vibration of the flow path forming member 200 during hydrogel manufacturing can be suppressed.

[0051] The hydrogel manufacturing apparatus 100 may also have a first inlet passage 132 that fluidly connects the first storage section 102 to the first flow path 212 of the flow path forming member 200, a second inlet passage 134 that fluidly connects the second storage section 104 to the second flow path 222 of the flow path forming member 200, and a third inlet passage 136 that fluidly connects the third storage section 106 to the third flow path 232 of the flow path forming member 200. These inlet passages 132, 134, and 136 may be formed, for example, within a non-flexible component or within a flexible tube. These inlet passages 132, 134, and 136 may be mounted in the housing 120 or disposed within the housing 120.

[0052] The hydrogel manufacturing apparatus 100 may include a first pump 112 for conveying a first fluid, a second pump 114 for conveying a second fluid, and a third pump 116 for conveying a third fluid. The first pump 112, the second pump 114, and the third pump 116 may be configured to adjust the flow rate and velocity of the first fluid, the second fluid, and the third fluid, respectively.

[0053] The flow rate settings of the first pump 112, the second pump 114, and the third pump 116 can be configured to be adjustable by the user or automatically adjusted by a pre-set program.

[0054] There is no particular limitation on the types of the first pump 112, the second pump 114, and the third pump 116. Preferably, the first pump 112, the second pump 114, and the third pump 116 can be pumps that reduce the pulsation of the delivered liquid. The first pump 112, the second pump 114, and the third pump 116 can be pumps with the following performance: except when the pump is started and stopped, within a specific average flow rate value, for example, within a specific average flow rate value in the range of 0.1 mL to 1000 mL / min, the variation in flow rate is, for example, within 20% of that specific average flow rate value, preferably within 10%, more preferably within 5%, and even more preferably within 2%.

[0055] The first inlet path 132 may have a first inlet valve 162 between the first storage section 102 and the first pulsation suppression unit 610 and / or the first defoaming unit 710 (described later). By activating the first pump 112 with the first inlet valve 162 open, the first fluid flows from the first storage section 102 toward the first inlet path 132. The flow path cross-sectional area of ​​the first inlet path 132 is preferably larger than that of the second inlet path 134 and / or the third inlet path 136. The first fluid flowing in the first inlet path 132 is a hydrogel precursor with relatively high viscosity. Therefore, if the flow path cross-sectional area of ​​the first inlet path 132 is large, it is easy to make the first fluid with high viscosity flow even without excessively increasing the pump pressure of the first pump 112. In this view, the first inlet path 132 may not be a single path, but rather branch into multiple paths in parallel. In this case, the flow path cross-sectional area of ​​the first inlet path 132 is defined by the sum of the cross-sectional areas of the multiple paths.

[0056] The second inlet path 134 may have a second inlet valve 164 between the second storage section 104 and the second pulsation suppression unit 620 and / or the second defoaming unit 720, which will be described later. By activating the second pump 114 with the second inlet valve 164 open, the second fluid flows from the second storage section 104 toward the second inlet path 134.

[0057] The third inlet path 136 may have a third inlet valve 166 between the third storage section 106 and the third pulsation suppression unit 630 and / or the third defoaming unit 730 described later. By activating the third pump 116 with the third inlet valve 166 open, the third fluid flows from the third storage section 106 toward the third inlet path 136.

[0058] The hydrogel manufacturing apparatus 100 may include a cleaning mechanism for cleaning at least a portion of the first flow path 212, the second flow path 222, and the third flow path 232. In a first embodiment, the hydrogel manufacturing apparatus 100 may include a cleaning container 108 for storing cleaning fluid. The cleaning fluid is preferably water, pure water, or saline solution. The second pump 114 may function not only as a pump for conveying the second fluid but also as a pump for conveying the cleaning fluid. Alternatively, a dedicated pump (cleaning pump) for conveying the cleaning fluid may be provided. In this case, the cleaning pump may be provided in the cleaning flow path 138, where essentially only the cleaning fluid flows.

[0059] The cleaning container 108 is preferably in fluid communication with at least one of the first flow path 212, the second flow path 222, and the third flow path 232 via the cleaning flow path 138. In the first embodiment, the cleaning container 108 merges with the second inlet path 134. Thus, the cleaning fluid can reach the outlet 240 through the cleaning flow path 138, the second inlet path 134, the second flow path 222, and the first merging point 216. Alternatively, the cleaning container 108 may also merge with the first inlet path 132. Furthermore, the cleaning container 108 may merge with both the first inlet path 132 and the second inlet path 134. In this case, the cleaning container 108 connected to the first inlet path 132 and the cleaning flow path 138 may be provided separately, as well as the cleaning container 108 connected to the second inlet path 134 and the cleaning flow path 138.

[0060] The cleaning flow path 138 may have a cleaning valve 168. By activating the cleaning pump and / or the second pump 114 with the cleaning valve 168 open, flow occurs from the cleaning container 108 toward the cleaning flow path 138 and the second inlet path 134.

[0061] The hydrogel manufacturing apparatus 100 may have a first air inlet 152, a second air inlet 154, and a third air inlet 156 that respectively introduce gas into a first inlet 132, a second air inlet 134, and a third air inlet 136. The first air inlet 152, the second air inlet 154, and the third air inlet 156 are respectively connected to the first air inlet 132, the second air inlet 134, and the third air inlet 136. The first air inlet 152, the second air inlet 154, and the third air inlet 156 are used to check for leaks in the first air inlet 132, the second air inlet 134, and the third air inlet 136.

[0062] The first inlet passage 132, the second inlet passage 134, and the third inlet passage 136 may each have an air valve 182, 184, and 186, respectively. By opening and closing the air valves 182, 184, and 186, it is possible to control whether gas is introduced into the first inlet passage 132, the second inlet passage 134, and the third inlet passage 136.

[0063] Here, by selectively opening the first inlet valve 162 and the air valve 182, it is possible to selectively determine whether to introduce the first fluid or gas into the first inlet passage 132. Similarly, by selectively opening the third inlet valve 166 and the air valve 186, it is possible to selectively determine whether to introduce the third fluid or gas into the third inlet passage 136.

[0064] Furthermore, by selectively opening the second inlet valve 164, the cleaning valve 168, and the air valve 184, it is possible to selectively determine whether to introduce the second fluid, the cleaning liquid, or the gas into the second inlet path 134.

[0065] The first inlet path 132 may also have a fourth inlet valve 172 located downstream of the confluence point of the first inlet path 132 and the first air inlet path 152. The second inlet path 134 may also have a fifth inlet valve 174 located downstream of the confluence point of the second inlet path 134 and the second air inlet path 154. The third inlet path 136 may also have a sixth inlet valve 176 located downstream of the confluence point of the third inlet path 136 and the third air inlet path 156.

[0066] Preferably, the fourth inlet valve 172 can be disposed between the flow path forming component 200 and the first pulsation suppression unit 610 and / or the first defoaming unit 710 described later. Preferably, the fifth inlet valve 174 can be disposed between the flow path forming component 200 and the second pulsation suppression unit 620 and / or the second defoaming unit 720 described later. Preferably, the sixth inlet valve 176 can be disposed between the flow path forming component 200 and the third pulsation suppression unit 630 and / or the third defoaming unit 730 described later.

[0067] The fourth inlet valve 172, the fifth inlet valve 174 and the sixth inlet valve 176 are used to prevent fluid from flowing back through the flow path forming member 200 to other inlet paths when fluid is flowing in any one of the first inlet path 132, the second inlet path 134 and the third inlet path 136.

[0068] The hydrogel manufacturing apparatus 100 may have a hydrogel flow path 300 and a receiving container 400. The receiving container 400 is a container for receiving the hydrogel formed by the contact between a first fluid (hydrogel precursor) and a second fluid (gelling agent). The receiving container 400 is not particularly limited and may be a container formed by the flow path forming component 200 that is suitable for the use environment and / or purpose of the hydrogel. More specifically, it may be a container pre-designed according to the use environment and / or purpose.

[0069] The hydrogel flow path 300 is a flow path that at least completely connects the receiving container 400 and the first confluence point 216. Preferably, the hydrogel flow path 300 completely connects the outlet 240 of the flow path forming component 200 to the receiving container 400. Here, the hydrogel flow path 300 is preferably configured to provide an airtight and / or liquidtight connection from the first confluence point 216 to the receiving container 400. Thus, the hydrogel formed by the contact between the first fluid (hydrogel precursor) and the second fluid (gelling agent) can be transferred in an airtight and / or liquidtight state to the receiving container 400 away from the flow path forming component 200. Therefore, it is possible to suppress the mixing of impurities into the formed hydrogel and the fluid flowing with the hydrogel.

[0070] The hydrogel flow path 300 may have a first end 310 that can be installed on the outlet 240 of the flow path forming component 200 and a second end 320 that can be attached to and detached from the inlet 410 of the receiving container 400. Thus, it is easy to connect the receiving container 400 and the outlet 240 of the flow path forming component 200, which are designed differently according to the hydrogel's usage environment and / or purpose.

[0071] The hydrogel flow path 300 is not particularly limited, and can have a length of, for example, 0.1m to 10m, 0.2m to 8m, or 0.4m to 5m. This allows the hydrogel to be transferred in a closed system to a receiving container 400 located relatively far from the flow path forming component 200.

[0072] The hydrogel flow path 300 can be constructed from a flexible tube or a rigid tube. When the hydrogel flow path 300 is constructed from a rigid tube, the shape of the hydrogel flow path 300 can be easily and stably maintained.

[0073] On the other hand, when the hydrogel flow path 300 is constructed of a flexible tube, even if the positional relationship between the flow path forming component 200 and the receiving container 400 changes, the hydrogel flow path 300 can maintain a closed connection between the receiving container 400 and the first confluence point 216 through the bending of the tube. When using a receiving container 400 with a design different from that corresponding to the hydrogel's usage environment and / or purpose, the placement of the receiving container 400 may sometimes be constrained. Even if the placement of the receiving container 400 changes due to this constraint, the closed connection between the receiving container 400 and the first confluence point 216 can be maintained through the hydrogel flow path 300, which is constructed of a flexible tube.

[0074] The inner diameter (diameter of the internal space) of the hydrogel flow path 300 is not particularly limited, and can be, for example, 1 to 400 times, preferably 1 to 100 times, more preferably 1 to 40 times, and even more preferably 1 to 10 times, the flow path (inner diameter) of the outlet 240 of the flow path forming component 200. Since the hydrogel formed in the flow path forming component 200 passes through, the inner diameter of the hydrogel flow path 300 is preferably more than 1 times the inner diameter of the outlet 240. In addition, in order to suppress the bending of the tubular hydrogel formed in the flow path forming component 200 in the hydrogel flow path 300, the upper limit of the hydrogel flow path 300 is preferably below the value desired above.

[0075] In the illustrated representation, the hydrogel flow path 300 consists of a single tube. Alternatively, the hydrogel flow path 300 can also be constructed by connecting multiple tubes in series.

[0076] There are no particular restrictions on the storage container 400, as long as it is a container suitable for the application environment and / or purpose of the hydrogel. Preferably, the storage container 400 is a flexible container with an internal space that can expand and contract.

[0077] In the absence of expansion and contraction of the internal space of the storage container 400, in order to suppress the increase of pressure in the internal space of the storage container 400 when the hydrogel formed by the flow path forming member 200 flows into the storage container 400, it is preferable to discharge the gas in the internal space of the storage container 400.

[0078] On the other hand, if the receiving container 400 is made of a flexible container with an internal space capable of expansion and contraction, the hydrogel can flow into the receiving container 400 while its internal space is concave. In this case, it is not necessary to expel gas from the internal space of the receiving container 400 during the process of allowing the hydrogel formed by the flow path forming member 200 to flow into the receiving container 400. Therefore, the possibility of impurities entering the receiving container 400 can be further reduced.

[0079] The hydrogel manufacturing apparatus 100 may include a first action unit 500 that moves the liquid within the receiving container 400. The first action unit 500 may be, for example, a stirrer for stirring the liquid within the receiving container 400, or a oscillating unit for oscillating the receiving container 400 itself.

[0080] Even if the first action unit 500 is an oscillating unit that makes the storage container 400 oscillate, as long as the hydrogel flow path 300 is made of a flexible tube, it has the advantage that the effect of the oscillation of the storage container 400 is difficult to be transmitted to the flow path forming component 200.

[0081] The storage container 400 may have: a discharge port 420 for discharging liquid from the internal space; and an inlet port 430 for introducing a liquid different from the liquid used during hydrogel formation into the internal space. By utilizing the discharge port 420 and the inlet port 430, the liquid stored in the internal space of the storage container 400 during hydrogel formation can be removed and / or replaced.

[0082] The first fluid and / or the third fluid may contain cells as suspended particles. When the third fluid contains cells, the cells can be contained within the space inside the formed tubular hydrogel. When the first fluid contains cells, the cells are embedded within the formed tubular hydrogel. In these cases, the receiving container 400 may be, for example, a culture container for culturing cells. In this case, the inlet port 430 may be a port for introducing culture medium into the receiving container 400.

[0083] There is no particular limitation on the type of cells. Such cells can be, for example, pluripotent ES cells, iPS cells, various pluripotent stem cells (hematopoietic stem cells, neural stem cells, mesenchymal stem cells, etc.), and single-differentiated stem cells (liver stem cells, germline stem cells, etc.). Alternatively, the cells contained in the first fluid can also be various differentiated cells, such as muscle cells such as skeletal muscle cells and cardiomyocytes, nerve cells such as cerebral cortex cells, fibroblasts, epithelial cells, hepatocytes, pancreatic β cells, and skin cells. In addition, it should be noted that "cell" is not limited to a single cell, and includes not only cellular tissues composed of multiple cells, but also microorganisms such as bacteria.

[0084] The first and / or third fluids may contain various growth factors suitable for cell culture, cell maintenance, proliferation, or cell functional expression, such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF), insulin-like growth factor (IGF), fibroblast growth factor (FGF), nerve growth factor (NGF), etc.

[0085] The hydrogel manufacturing apparatus 100 may include a first pulsation suppression unit 610, a second pulsation suppression unit 620, and / or a third pulsation suppression unit 630. The first pulsation suppression unit 610 is a unit for suppressing pulsation of a first fluid generated by a first pump 112. The second pulsation suppression unit 620 is a unit for suppressing pulsation of a second fluid generated by a second pump 114. The third pulsation suppression unit 630 is a unit for suppressing pulsation of a third fluid generated by a third pump 116.

[0086] The first pulsation suppression unit 610 can be disposed upstream of the first confluence point 216, preferably upstream of the second confluence point 226, and more preferably upstream of the flow path forming component 200. The second pulsation suppression unit 620 can be disposed upstream of the first confluence point 216, preferably upstream of the flow path forming component 200. The third pulsation suppression unit 630 can be disposed upstream of the second confluence point 226, preferably upstream of the flow path forming component 200.

[0087] The pulsation suppression units 610, 620, and 630 may include any unit for suppressing pulsation. By suppressing the pulsation of the first fluid, the second fluid, and / or the third fluid, the first fluid, the second fluid, and / or the third fluid hardly mix with other fluids at the first confluence point 216 and / or the second confluence point 226, respectively, easily forming a clean laminar flow. Therefore, deviations in the shape of the ultimately formed hydrogel can be suppressed.

[0088] The hydrogel manufacturing apparatus 100 may include a first defoaming unit 710, a second defoaming unit 720, and / or a third defoaming unit 730. The first defoaming unit 710 is a unit for removing gas (bubbles) from a first fluid. The second defoaming unit 720 is a unit for removing gas (bubbles) from a second fluid. The third defoaming unit 730 is a unit for removing gas (bubbles) from a third fluid.

[0089] The first defoaming unit 710 can be disposed upstream of the first confluence point 216, preferably upstream of the second confluence point 226, and more preferably upstream of the flow path forming component 200. The second defoaming unit 720 can be disposed upstream of the first confluence point 216, preferably upstream of the flow path forming component 200. The third defoaming unit 730 can be disposed upstream of the second confluence point 226, preferably upstream of the flow path forming component 200.

[0090] By removing foam from the first fluid, the second fluid, and / or the third fluid, the first fluid, the second fluid, and / or the third fluid can easily form a regular laminar flow at the first confluence point 216 and / or the second confluence point 226, respectively. This allows for the suppression of deviations in the shape of the final hydrogel.

[0091] The first pulsation suppression unit 610 and the first defoaming unit 710 can be independent units or the same unit. When the first pulsation suppression unit 610 and the first defoaming unit 710 are the same unit, both the suppression of pulsation in the first fluid and the removal of bubbles in the first fluid can be achieved through a single unit. Similarly, the second pulsation suppression unit 620 and the second defoaming unit 720 can be independent units or the same unit. Furthermore, the third pulsation suppression unit 630 and the third defoaming unit 730 can be independent units or the same unit.

[0092] In the illustrated configuration, the first pulsation suppression unit 610 and the first debubbling unit 710 are composed of the same unit, i.e., a common unit. Similarly, the second pulsation suppression unit 620 and the second debubbling unit 720 are composed of the same unit, i.e., a common unit. Furthermore, the third pulsation suppression unit 630 and the third debubbling unit 730 are composed of the same unit, i.e., a shared unit.

[0093] In the illustrated example, the first pulsation suppression unit 610 and the first defoaming unit 710 are located between the first pump 112 and the first confluence point 216, preferably between the first pump 112 and the flow path forming component 200. The first pulsation suppression unit 610 and the first defoaming unit 710 have a gas receiving portion 612 capable of holding the gas.

[0094] The receiving section 612 communicates with the first inlet passage 132 and can be sealed off outside the first inlet passage 132. The first fluid, supplied from the first pump 112 to the receiving section 612 via the first inlet passage 132, is temporarily stored in the receiving section 612. Air bubbles in the first fluid temporarily stored in the receiving section 612 are stored within the receiving section 612. The portion of the first inlet passage 132 below the receiving section 612 communicates with the receiving section 612. Therefore, air bubbles stored in the receiving section 612 are unlikely to mix into the flow path forming member 200.

[0095] Furthermore, when the first fluid is stored in the receiving section 612 and the pressure inside the receiving section 612 increases, the first fluid is supplied from the receiving section 612 to the flow path forming member 200. Since the pressure fluctuation in the receiving section 612 is smaller than the pulsation of the first pump 112, the first fluid is supplied to the flow path forming member 200 while the pulsation of the first fluid caused by the first pump 112 is suppressed.

[0096] The first pulsation suppression unit 610 and the first defoaming unit 710 preferably have a pressure sensor 616 for measuring the pressure within the receiving section 612. After the pressure detected by the pressure sensor 616 reaches the desired value, the first fluid can be appropriately delivered toward the flow path forming member 200 by opening the fourth inlet valve 172.

[0097] In the illustrated example, the second pulsation suppression unit 620 and the second defoaming unit 720 are located between the second pump 122 and the first confluence point 216, preferably between the second pump 122 and the flow path forming component 200. The structures of the second pulsation suppression unit 620 and the second defoaming unit 720 are the same as those of the first pulsation suppression unit 610 and the first defoaming unit 710, therefore their description is omitted.

[0098] In the illustrated example, the third pulsation suppression unit 630 and the third defoaming unit 730 are located between the third pump 116 and the second confluence point 226, preferably between the third pump 116 and the flow path forming component 200. The structures of the third pulsation suppression unit 630 and the third defoaming unit 730 are the same as those of the first pulsation suppression unit 610 and the first defoaming unit 710, so their description is omitted.

[0099] The hydrogel manufacturing apparatus 100 may include a camera unit 800. The camera unit 800 may be configured to capture the morphology of the hydrogel downstream of the first confluence point 216 or at the first confluence point 216. Preferably, the camera unit 800 may be configured to capture the morphology of the hydrogel downstream of the outlet 240 of the flow path forming member 200, i.e., in the hydrogel flow path 300.

[0100] The camera unit 800 captures the morphology of the hydrogel as an image (including still images or moving images). Preferably, the image captured by the camera unit 800 is sent to the control device 900, which will be described later.

[0101] Figure 4 This is a perspective view showing an example of the structure of the hydrogel formed in the first embodiment. Figure 5 yes Figure 4 A cross-sectional view of the hydrogel is shown. Figure 4 As shown, the hydrogel 10 is formed into a long, extended tubular shape. Hereinafter, the tubular hydrogel is sometimes referred to as the "shell 14". In addition, the inner part of the tubular hydrogel, that is, the part formed by the first fluid, is sometimes referred to as the "core 12".

[0102] When the receiving container 400 is made of a flexible container with an internal space that can expand and contract, it is preferable that, during the manufacture of the hydrogel, before the first fluid, the second fluid, and the third fluid are delivered, the internal space of the receiving container 400 is in an expandable state as described above.

[0103] The hydrogel manufacturing apparatus 100 may include a control device 900 for controlling the various components of the apparatus. The control device 900 may include an input unit 910, a parsing unit 920, an instruction unit 930, and a storage unit 940.

[0104] The control device 900 can also control, for example, the control of the first pump 112, the second pump 114, the third pump 116, the first inlet valve 162, the second inlet valve 164, the third inlet valve 166, the fourth inlet valve 172, the fifth inlet valve 174, the sixth inlet valve 176, the cleaning valve 168, and / or the air valves 182, 184, and 186.

[0105] The control device 900 may include a CPU (Central Processing Unit), ROM (Read-Only Memory), and RAM (Random Access Memory). The CPU is an arithmetic unit. A detailed example of the control of the control device 900 is described below. The ROM stores programs that implement various processes of the CPU. Such programs may be, for example, programs used to execute the various controls described in the foregoing embodiments. The RAM stores data required for various processes of the CPU.

[0106] The input unit 910 accepts input from the user using the hydrogel manufacturing apparatus 100. The input unit 910 accepts input from input devices such as keyboards, mice, or touch screens.

[0107] In one example, the input unit 910 may be configured to accept set values ​​for the flow rates of the first flow path, the second flow path, and the third flow path, respectively. In other words, the user can input the flow rates of the first fluid, the second fluid, and the third fluid from the input device.

[0108] The input unit 910 is preferably configured to receive the flow rate of the first flow path, the flow rate of the second flow path, and the flow rate of the third flow path respectively. However, the input unit 910 may also be configured to receive any one or two of the set values ​​of the flow rate of the first flow path, the flow rate of the second flow path, and the flow rate of the third flow path.

[0109] The instruction unit 930 sends instructions to operate the first pump 112, the second pump 114, and the third pump 116. Upon receiving set values ​​for the flow rates of the first fluid, the second fluid, and the third fluid from the input unit 910, the instruction unit 930 operates the first pump 112, the second pump 114, and the third pump 116 based on the input flow rate set values. Thus, the flow rates of the first fluid, the second fluid, and the third fluid can be set and / or changed according to the user's request for flow rate set values.

[0110] Here, the flow rates of the first, second, and third fluids affect values ​​related to the size of the formed tubular hydrogel. Specifically, the flow rates V1, V2, and V3 of the first, second, and third fluids affect the diameter of the shell (the overall diameter of the hydrogel) R1, the diameter of the core R2, and the ratio of the cross-sectional area S3 of the core to the cross-sectional area S1 of the shell (S3 / S1) in the formed tubular hydrogel (see also...). Figure 5 Here, the cross-sectional area is the area of ​​the cross section in the direction orthogonal to the length direction of the tube. For example, the flow velocities of the first fluid, the second fluid, and the third fluid are related to the diameter R1 of the shell, the diameter R2 of the core, and the ratio (S3 / S1) of the cross-sectional area S3 of the core to the cross-sectional area S1 of the shell in the tubular hydrogel as shown in Table 1 below. In Table 1 below, it should be noted that the "reference" is only used as a reference for comparison with Examples 1 to 3.

[0111] (Table 1)

[0112]

[0113] More specifically, if the flow rates of the first and third fluids are not changed, but the flow rate of the second fluid is increased, the diameters of both the shell (R1) and the core (R2) decrease (comparison of the baseline and Example 1 in Table 1). However, the ratio of the cross-sectional area S3 of the core to the cross-sectional area S1 of the shell (S3 / S1) remains almost unchanged. Furthermore, if the flow rates of the second and third fluids are not changed, but the flow rate of the first fluid is increased, the diameter of the shell (R1) increases, and the ratio of the cross-sectional area S3 of the core to the cross-sectional area S1 of the shell (S3 / S1) decreases (comparison of the baseline and Example 2 in Table 1). Moreover, if the flow rates of the first and second fluids are not changed, but the flow rate of the third fluid is increased, the diameters of both the shell (R1) and the core (R2) increase, and the ratio of the cross-sectional area S3 of the core to the cross-sectional area S1 of the shell (S3 / S1) also increases (comparison of the baseline and Example 3 in Table 1).

[0114] Therefore, by appropriately setting the flow rates V1 of the first fluid, V2 of the second fluid, and V3 of the third fluid, the user can appropriately adjust the diameter R1 of the shell, the diameter R2 of the core, and the ratio (S3 / S1) of the cross-sectional area S3 of the core to the cross-sectional area S1 of the shell in the formed tubular hydrogel.

[0115] The control device 900 can acquire image data of the hydrogel obtained by the camera unit 800. The analysis unit 920 can be configured to analyze the morphology of the hydrogel captured by the camera unit 800.

[0116] The analysis unit 920 analyzes the image of the hydrogel transferred into the image using known image analysis processing. Preferably, the analysis unit 920 calculates values ​​related to the size of the formed hydrogel. Specifically, the analysis unit 920 preferably calculates the diameter R1 of the shell, the diameter R2 of the core, and / or the ratio (S3 / S1) of the cross-sectional area S3 of the core to the cross-sectional area S1 of the shell in the formed hydrogel.

[0117] The storage unit 940 can store the results analyzed by the analysis unit 920 together with the set value of the flow rate set by the input unit 910. Preferably, the values ​​related to the size of the hydrogel calculated by the analysis unit 920 and the information related to the flow rates V1 of the first fluid, V2 of the second fluid and V3 of the third fluid during the manufacture of the hydrogel are stored in the storage unit 940 in association.

[0118] Figure 6 This is a diagram illustrating an example of the data stored in the storage unit in the first embodiment. For example... Figure 6 As shown, the diameter R1 of the shell, the diameter R2 of the core, and the ratio (S3 / S1) of the cross-sectional area S3 of the core to the cross-sectional area S1 of the shell in the hydrogel calculated by the analysis unit 920 can be stored in the storage unit 940 in association with the flow rates V1 of the first fluid, V2 of the second fluid, and V3 of the third fluid during the manufacture of the hydrogel.

[0119] The information on the size and flow rate of the hydrogel stored in storage unit 940 can be configured to allow the user to confirm information based on user instructions. For example, Figure 6 The information can be displayed on a display device 980, such as a monitor, provided in the hydrogel manufacturing apparatus 100. In this case, when manufacturing a new hydrogel, the user can easily set an appropriate flow rate value based on data of the size of previously formed hydrogels.

[0120] In the above description, the cases where the input unit 910 receives the flow rates of the first flow path, the second flow path, and the third flow path have been explained. However, the input unit 910 may also be configured to receive information related to the size of the hydrogel to be formed. For example, the input unit 910 may also be configured to receive the diameter R1 of the shell, the diameter R2 of the core, etc., in the hydrogel to be formed.

[0121] When the control device 900 receives user-inputted information related to the size of the hydrogel to be formed, such as the diameter R1 of the shell and the diameter R2 of the core, the control device 900 automatically determines the flow rates V1 of the first fluid, V2 of the second fluid, and V3 of the third fluid based on the information related to the size of the hydrogel. The flow rates V1, V2, and V3 of the first fluid can be obtained, for example, based on information about the size of hydrogels manufactured in the past. Specifically, the control device 900 can use past data stored in the storage unit 940 (see reference...) Figure 6 The relationship between the flow velocities V1, V2, and V3 of the first fluid and the size (diameters R1 and R2) of the hydrogel is determined to establish the flow velocities V1, V2, and V3 of the first fluid.

[0122] In this case, the command unit 930 of the control device 900 can control the flow rates of the first fluid, the second fluid, and the third fluid according to the determined flow rate values ​​V1, V2, and V3, that is, control the first pump 112, the second pump 114, and the third pump 116.

[0123] Furthermore, the control device 900 can also be configured to control (feedback control) the flow rate of at least one of the first fluid (hydrogel precursor), the second fluid (gelling agent), and the third fluid based on the results analyzed by the analysis unit 920. Specifically, as described above, the analysis unit 920 calculates information related to the size of the actually formed hydrogel (e.g., various diameters R1, R2) based on an image of the formed hydrogel. Furthermore, the analysis unit 920 calculates the deviation between the information related to the size of the actually formed hydrogel (e.g., various diameters R1, R2) and the information related to the size of the hydrogel received by the input unit 910. The instruction unit 930 can eliminate this deviation simply by controlling and changing the flow rate of at least one of the first fluid (hydrogel precursor), the second fluid (gelling agent), and the third fluid.

[0124] As described above, the flow rates of the first fluid, the second fluid, and the third fluid have the relationship shown in Table 1 with respect to the diameter R1 of the shell, the diameter R2 of the core, and / or the ratio (S3 / S1) of the cross-sectional area S3 of the core to the cross-sectional area S1 of the shell. Based on this relationship, the control device 900 can change the flow rate of at least one of the first fluid, the second fluid, and the third fluid in a manner that makes the size of the actually formed hydrogel close to the set value of the size of the hydrogel input by the user.

[0125] Instead of the above analysis, or based on the above analysis, the analysis unit 920 may be configured to estimate the density of inclusions, such as cells, within the formed hydrogel based on image information captured by the imaging unit 800. The image information used to estimate the cell density may be, for example, optical information and / or transparency information. In one example, the analysis unit 920 may be configured to calculate the transparency of the image captured by the imaging unit 800, or in addition to the above analysis, and estimate the density of inclusions, such as cells, within the hydrogel based on this transparency. Specifically, in the case where the third fluid contains cells, the analysis unit 920 calculates the transparency of the nucleus within the hydrogel in the image captured by the imaging unit 800. Based on the transparency of the nucleus, the analysis unit 920 estimates the cell density within the nucleus of the hydrogel.

[0126] When the third fluid includes cells, the transparency of the third fluid or nucleus is closely related to the density of cells in the third fluid. That is, the higher the density of cells in the third fluid, the lower the transparency of the third fluid or nucleus. Therefore, the analysis unit 920 can estimate the cell density within the nucleus of the hydrogel based on the transparency of the nucleus in the formed hydrogel. The relationship between nucleus transparency and cell density can be determined experimentally in advance. Thus, the hydrogel manufacturing apparatus 100 can quantitatively measure and store the density of cells mixed in the hydrogel, for example, in experimental applications such as cell culture.

[0127] The analysis unit 920 can also be configured to detect an anomaly in at least one of the hydrogel, the first flow path 212, and the second flow path 222 by analyzing the image (image information) captured by the camera unit 800. The control device 900 can be configured to stop the delivery of at least one of the first fluid (hydrogel precursor), the second fluid (gelling agent), and the third fluid when the above-mentioned anomaly is detected, preferably stopping all delivery.

[0128] Alternatively, the analysis unit 920 can also be configured to detect anomalies in the third flow path 232 by analyzing the images (image information) captured by the camera unit 800. In this case, the control device 900 can be configured to stop the delivery of at least one, preferably all, of the first fluid (hydrogel precursor), the second fluid (gelling agent), and the third fluid when an anomaly is detected.

[0129] Here, in the event of detecting an anomaly in the first flow path 212, the second flow path 222, and / or the third flow path 232, the camera unit 800 may be configured to capture an image of at least one of the first flow path 212, the second flow path 222, and the third flow path 232.

[0130] Anomalies detected in the hydrogel may include abnormalities in the size of the hydrogel, significant deviations in the shape of the hydrogel, and / or failure to form a hydrogel. Anomalies detected in the first flow path 212, the second flow path 222, and the third flow path 232 may include blockage of the flow path, turbulence in the flow, and deviations in the coaxial flow of the first, second, and third fluids.

[0131] Alternatively, the control device 900 may be configured to, for example, stop the delivery of at least one, preferably all, of the first fluid (hydrogel precursor), the second fluid (gelling agent), and the third fluid when an abnormal pressure is detected in at least one of the flow paths 212, 222, and 232. The abnormal pressure can be detected, for example, by the pressure sensor 616 described above.

[0132] If the analysis unit 920 detects an abnormality in the hydrogel that should be formed, the control device 900 may be configured to stop the delivery of the first fluid (hydrogel precursor), the second fluid (gelling agent), and / or the third fluid.

[0133] The display device 980 may be configured to display a schematic diagram of at least one flow path, preferably multiple flow paths, and more preferably all flow paths, selected from the first flow path 212, the second flow path 222, the third flow path 232, the first inlet path 132, the second inlet path 134, the third inlet path 136, and the cleaning flow path 138. Preferably, the display device 980 may display the status of each flow path together with the flow path.

[0134] (Methods for manufacturing hydrogels)

[0135] Next, refer to Figures 7-13 The manufacturing method of hydrogel is explained. Figure 7 This is a diagram illustrating the status of each import path in the initial stage of leak detection. Figure 8 This is an explanation of what follows. Figure 7 A diagram illustrating the status of each import path during the stages. Figure 9 This is an explanation of what follows. Figure 8 A diagram illustrating the status of each import path during the stages. Figure 10 This is a schematic diagram illustrating the status of each inlet path during the pre-liquid delivery stage. Figure 11 This is a schematic diagram illustrating the state of each introductory path during the preparation phase of the pulsation suppression unit and / or debubbling unit. Figure 12 This is an explanation of what follows. Figure 11 A diagram illustrating the status of each import path during the stages. Figure 13 This is a schematic diagram illustrating the state of each pathway in the stages of hydrogel formation.

[0136] (1) Preparation

[0137] In the method for manufacturing hydrogel, firstly, a flow path forming component 200 is disposed on a frame 120. Specifically, the first flow path 212 of the flow path forming component 200 is connected to the first inlet path 132, the second flow path 222 of the flow path forming component 200 is connected to the second inlet path 134, and the third flow path 232 of the flow path forming component 200 is connected to the third inlet path 136.

[0138] Additionally, a first fluid is added to the first storage section 102, a second fluid is added to the second storage section 104, and a third fluid is added to the third storage section 106. Cleaning fluid is added to the cleaning container 108 as needed.

[0139] Here, the hydrogel flow path 300 and the receiving container 400 may not be connected to the flow path forming component 200. Instead, it is preferable that the outlet 240 side of the flow path forming component 200 is sealed.

[0140] (2) Leakage inspection

[0141] Next, a leak check is performed on the first inlet path 132, the second inlet path 134, and the third inlet path 136. Specifically, it is confirmed that the first inlet path 132, the second inlet path 134, and the third inlet path 136 are airtight and / or liquidtight. Alternatively, or based on this, it is confirmed that the flow path forming component 200 is airtightly and / or liquidtightly connected to the first inlet path 132, the second inlet path 134, and the third inlet path 136.

[0142] In the initial stage of leak inspection, all the aforementioned valves, namely the first inlet valve 162, the second inlet valve 164, the third inlet valve 166, the fourth inlet valve 172, the fifth inlet valve 174, the sixth inlet valve 176, the cleaning valve 168, and the air valves 182, 184, and 186, can be in the closed state (see reference). Figure 7 Here, in Figures 7-13 In the diagram, a valve that is shaded in black indicates that the valve is closed. On the other hand, a valve that is not shaded in black indicates that the valve is open.

[0143] Next, open air valves 182, 184, and 186 to activate the first pump 112, the second pump 114, and the third pump 116, thereby introducing gas into the first inlet passage 132, the second inlet passage 134, and the third inlet passage 136 to check for leaks (refer to...). Figure 8 Here, in Figures 7-13 In the diagram, the flow path and the inlet path, which are coated with dots, represent the introduction of gas.

[0144] More specifically, it is confirmed whether there is leakage in the upstream portions of the first inlet passage 132, the second inlet passage 134, and the third inlet passage 136 compared to the fourth inlet valve 172, the fifth inlet valve 174, and the sixth inlet valve 176.

[0145] Next, open the fourth inlet valve 172 and check for leakage on the downstream side of the first inlet passage 132 compared to the fourth inlet valve 172 (refer to...). Figure 9 Here, the first inlet path 132 is connected to the second inlet path 134 and the third inlet path 136 via the flow path forming component 200, so the fifth inlet valve 174 and the sixth inlet valve 176 can be closed. This allows for confirmation, in particular, of whether the first flow path 212 and the first inlet path 132 are in airtight and / or liquidtight communication.

[0146] Additionally, close the fourth inlet valve 172 and open the fifth inlet valve 174 to check for leaks at a location downstream of the fifth inlet valve 174 in the second inlet path 134. At this time, the fourth inlet valve 172 and the sixth inlet valve 176 can be closed. This allows for confirmation, in particular, of whether the second flow path 222 and the second inlet path 134 are in airtight and / or liquidtight communication.

[0147] Additionally, close the fifth inlet valve 174 and open the sixth inlet valve 176 to check for leaks at a location downstream of the sixth inlet valve 176 in the third inlet path 136. At this time, the fourth inlet valve 172 and the fifth inlet valve 174 can be closed. This allows for confirmation, in particular, of whether the third flow path 232 and the third inlet path 136 are in airtight and / or liquidtight communication.

[0148] Here, the confirmation of leaks in the first inlet path 132, the second inlet path 134, and the third inlet path 136 can be performed in any order. Furthermore, the occurrence of leaks in each inlet path can be detected, for example, by measuring the pressure value or pressure variation value measured by the pressure sensor 616 connected to each inlet path.

[0149] After the leak inspection is completed, close all the above valves, namely the first inlet valve 162, the second inlet valve 164, the third inlet valve 166, the fourth inlet valve 172, the fifth inlet valve 174, the sixth inlet valve 176, the cleaning valve 168, and the air valves 182, 184, and 186.

[0150] (3) Deliver liquid in advance (pre-delivery)

[0151] Next, the outlet 240 of the flow path forming component 200 and the receiving container 400 are connected in an airtight and / or liquid-tight manner using the hydrogel flow path 300. Then, liquid is pre-delivered to the receiving container 400 through the hydrogel flow path 300 (pre-liquid delivery).

[0152] In the pre-feeding process, the cleaning fluid is preferably fed into the receiving container 400 through the outlet 240 of the flow path forming component 200 and the hydrogel flow path 300. Specifically, the cleaning valve 168 and the fifth inlet valve 174 are opened, and the second pump 114 is driven to deliver the cleaning fluid (see reference). Figure 10 ).exist Figure 10 The flow path depicting the smearing pattern indicates the part where the cleaning fluid is introduced.

[0153] The cleaning fluid reaches the outlet 240 through the cleaning flow path 138, the second inlet path 134, the second flow path 222, and the first confluence point 216. Then, the cleaning fluid reaches the receiving container 400 through the hydrogel flow path 300.

[0154] The purpose of the pre-feeding liquid is to wet the inner surface of the tube constituting the hydrogel flow path 300. This prevents the hydrogel formed in subsequent stages from adhering to the inner surface of the tube constituting the hydrogel flow path 300.

[0155] In the above embodiment, during the pre-feeding stage, the cleaning solution is delivered via a hydrogel flow path. Alternatively, the fluid flowing through the hydrogel flow path during the pre-feeding stage can be a liquid other than the cleaning solution. For example, the fluid flowing through the hydrogel flow path can be any one of a first fluid, a second fluid, and a third fluid. To suppress cell loss and reduce costs, the fluid flowing through the hydrogel flow path is preferably the cleaning solution or the second fluid.

[0156] After the pre-flushing is completed, simply close all the above valves, namely the first inlet valve 162, the second inlet valve 164, the third inlet valve 166, the fourth inlet valve 172, the fifth inlet valve 174, the sixth inlet valve 176, the cleaning valve 168, and the air valves 182, 184, and 186.

[0157] (4) Preparation of pulsation suppression unit and / or defoaming unit

[0158] The preparation of the pulsation suppression unit and / or defoaming unit is performed as needed, and can be omitted if not required. In this preparation, the first inlet valve 162, the second inlet valve 164, and the third inlet valve 166 are opened, causing the first pump 112, the second pump 114, and the third pump 116 to operate and deliver the first fluid, the second fluid, and the third fluid (…). Figure 11 The first fluid, the second fluid, and the third fluid are respectively sent to the receiving section 612 constituting the pulsation suppression units 610, 620, 630 and / or the debubbling units 710, 720, 730. Figure 11 The flow path depicted in the text represents the portion where a first fluid, a second fluid, or a third fluid is introduced.

[0159] When the first fluid, the second fluid, and the third fluid are delivered to the receiving section 612, the pressure inside the receiving section 612 increases. Next, as... Figure 12 As shown, open the valve located in the pressure sensor 616 to adjust the pressure within the receiving section 612 to the desired range (see reference). Figure 12 After this stage is completed, simply close the valve located on the pressure sensor 616.

[0160] (5) Stages in the formation of hydrogels

[0161] Next, a hydrogel is formed. The hydrogel manufacturing method using the above-described hydrogel manufacturing apparatus includes: flowing a third fluid toward a third flow path 232; flowing a first fluid (hydrogel precursor) toward a first flow path 212; flowing a second fluid (gelling agent) toward a second flow path 222; and merging the hydrogel precursor and the gelling agent at a first confluence point 216 to form a hydrogel.

[0162] Specifically, opening the first inlet valve 162, the second inlet valve 164, the third inlet valve 166, the fourth inlet valve 172, the fifth inlet valve 174, and the sixth inlet valve 176 activates the first pump 112, the second pump 114, and the third pump 116, delivering the first fluid, the second fluid, and the third fluid (see reference). Figure 13 Preferably, the second actuation unit 107 can be activated before the third fluid is dispensed, causing the third fluid in the third storage section 106 to move (oscillate or vibrate, etc.). When the third fluid includes suspended particles such as cells, the action of the second actuation unit 107 can make the suspended particles in the third fluid uniformly dispersed.

[0163] Preferably, the first fluid, the second fluid, and the third fluid are continuously supplied at constant flow rates. Thus, at the first confluence point 216, a laminar flow is formed in which the third fluid, the first fluid, and the second fluid are arranged sequentially from the center outwards in the radial direction. In this state, the first fluid (hydrogel precursor) is gelled by the second fluid (gelling agent), thereby forming a tubular hydrogel containing the first fluid internally (see reference). Figure 4 and Figure 5 Here, the length of the tubular hydrogel can be adjusted by the delivery time of the first, second, and third fluids.

[0164] The hydrogel formed by the flow path forming component 200 is introduced into the receiving container 400 through the hydrogel flow path 300.

[0165] [Second Implementation]

[0166] Figure 14 This is a schematic diagram illustrating the structure of the flow path of the hydrogel manufacturing apparatus in the second embodiment. Figure 15 This is a block diagram of the hydrogel manufacturing apparatus according to the second embodiment. It should be noted that in the second embodiment, descriptions of structures identical to those in the first embodiment are sometimes omitted. Furthermore, the same reference numerals are used for structures that are identical or corresponding to those described in the first embodiment.

[0167] In the second embodiment, the hydrogel manufacturing apparatus 100 may include a first storage section 102, a second storage section 104, and a flow path component 200. The first storage section 102 stores a first fluid. The first fluid is a hydrogel precursor. Details regarding the hydrogel precursor are as described in the first embodiment.

[0168] The second storage section 104 stores a second fluid (gelling agent) that gels the first fluid (hydrogel precursor) through contact with the first fluid. Details regarding the gelling agent are as described in the first embodiment.

[0169] The flow path component 200 is a component that includes a first fluid flow path and a second fluid flow path. The flow path component 200 may have a first inlet 210, a second inlet 220, and an outlet 240. The first inlet 210 is the inlet for the first fluid. The second inlet 220 is the inlet for the second fluid. The flow path component 200 may have a first flow path 212 and a second flow path 222.

[0170] It should be noted that the third storage unit 106 and the third flow path, which were not described in the first embodiment, are not present in the second embodiment.

[0171] The first flow path 212 is the flow path for the hydrogel precursor, which can be defined by a flow path from the first inlet 210 through the first confluence point 216 (described later) to the outlet 240. The second flow path 222 can be defined by a flow path from the second inlet 220 to the first confluence point 216.

[0172] The second flow path 222 is configured such that the second fluid (gelling agent) merges with the first fluid in the first flow path 212 at the first confluence point 216. Thus, the second fluid flows around the flow of the first fluid in the direction of its flow. That is, the second fluid surrounds the first fluid (hydrogel precursor) in a cross-section orthogonal to the flow of the first fluid.

[0173] The hydrogel manufacturing apparatus 100 may have a first pump 112 for conveying a first fluid and a second pump 114 for conveying a second fluid.

[0174] The hydrogel manufacturing method using the hydrogel manufacturing apparatus of the second embodiment includes: flowing a first fluid (hydrogel precursor) into a first flow path 212; flowing a second fluid (gelling agent) into a second flow path 222; and merging the hydrogel precursor and the gelling agent at a first confluence point 216 to form a hydrogel.

[0175] Preferably, the first fluid and the second fluid are continuously supplied at constant flow rates. Thus, at the first confluence point 216, a laminar flow is formed in which the first and second fluids are arranged sequentially from the center outwards in the radial direction. In this state, the first fluid (hydrogel precursor) is gelled by the second fluid (gelling agent), thereby forming a rope-like hydrogel (a solid hydrogel) (see reference). Figure 16 and Figure 17 ).

[0176] The hydrogel formed by the flow path forming component 200 is introduced into the receiving container 400 through the hydrogel flow path 300.

[0177] Figure 16 This is a perspective view showing an example of the structure of the hydrogel formed in the second embodiment. Figure 17 yes Figure 16 A cross-sectional view of the hydrogel is shown. Figure 16 As shown, the solid hydrogel 10 is formed into a long, extended rope shape.

[0178] The first fluid may contain cells. When the first fluid contains cells, the cells are embedded in the formed rope-like hydrogel. In this case, the receiving container 400 may be, for example, a culture container for culturing cells. The types of cells are as described in the first embodiment.

[0179] The hydrogel manufacturing apparatus 100 may include a first pulsation suppression unit 610 and / or a second pulsation suppression unit 620. Additionally, the hydrogel manufacturing apparatus 100 may include a first defoaming unit 710 and / or a second defoaming unit 720. The structures of the first pulsation suppression unit 610, the second pulsation suppression unit 620, the first defoaming unit 710, and / or the second defoaming unit 720 are as described in the first embodiment.

[0180] In one example of the second embodiment, the input unit 910 may be configured to receive set values ​​for the flow rate of the first flow path and the flow rate of the second flow path, respectively. In other words, the user can input the flow rate of the first fluid and the flow rate of the second fluid from the input device. Alternatively, the input unit 910 may also be configured to receive one of the flow rates of the first flow path and the second flow path. The instruction unit 930 sends an instruction to operate the first pump 112 and the second pump 114 based on the input value received by the input unit 910.

[0181] Here, the flow rates of the first and second fluids influence values ​​related to the size of the formed rope-like hydrogel. Specifically, the flow rates V1 and V2 of the first and second fluids affect the diameter R1 of the formed tubular hydrogel. More specifically, the larger the ratio of the flow rates of the first and second fluids (V1 / V2), the larger the diameter R1 of the hydrogel.

[0182] Therefore, by appropriately setting the flow rate V1 of the first fluid and the flow rate V2 of the second fluid, the user can appropriately adjust the diameter R1 of the formed rope-like hydrogel.

[0183] The analysis unit 920 can calculate values ​​related to the size of the formed hydrogel. Specifically, the analysis unit 920 preferably calculates the diameter R1 of the formed hydrogel.

[0184] Storage unit 940 can associate the results analyzed by analysis unit 920 with the flow rate value set by input unit 910. Values ​​related to the size of the hydrogel, such as diameter R1, calculated by analysis unit 920 are preferably associated with information related to the flow rate V1 of the first fluid and the flow rate V2 of the second fluid during the manufacture of the hydrogel and stored in storage unit 940.

[0185] Figure 18 This is a diagram illustrating an example of the data stored in the storage unit in the second embodiment. For example... Figure 18 As shown, the diameter R1 of the hydrogel calculated by the analysis unit 920 can be stored in the storage unit 940 in association with the flow rate V1 of the first fluid and the flow rate V2 of the second fluid during the manufacture of the hydrogel.

[0186] Similar to the first embodiment, the input unit 910 may also be configured to accept information related to the size of the hydrogel to be formed. For example, the input unit 910 may also be configured to accept the diameter R1 of the hydrogel to be formed.

[0187] When the control device 900 receives information input by the user related to the size of the hydrogel to be formed, such as the diameter R1 of the hydrogel, the control device 900 automatically determines at least one of the flow rate V1 of the first fluid and the flow rate V2 of the second fluid based on the information related to the size of the hydrogel. The flow rate V1 of the first fluid and the flow rate V2 of the second fluid can be obtained, for example, based on information about the size of hydrogels manufactured in the past. Specifically, the control device 900 can base its decisions on past data stored in the storage unit 940 (see [reference]). Figure 10The relationship between the flow rates V1 and V2 of the first fluid and the size (diameter R1) of the hydrogel is used to determine at least one of the flow rates V1 and V2 of the first fluid. Alternatively, the control device 900 may determine only one of the flow rates V1 and V2 of the first fluid based on information input by the user related to the size of the hydrogel to be formed, such as the diameter R1 of the hydrogel, while the user determines the other of the flow rates V1 and V2.

[0188] The control device 900 can be configured to control (feedback control) the flow rate of at least one of the first fluid (hydrogel precursor) and the second fluid (gelling agent) based on the results analyzed by the analysis unit 920. Specifically, as described above, the analysis unit 920 calculates the actual diameter R1 of the formed hydrogel based on an image of the formed hydrogel. Furthermore, the analysis unit 920 calculates the deviation between the actual diameter R1 of the formed hydrogel and the set value of the hydrogel diameter received by the input unit 910. The instruction unit 930 can eliminate this deviation simply by controlling, i.e., changing the flow rate of at least one of the first fluid (hydrogel precursor) and the second fluid (gelling agent).

[0189] As described above, the larger the ratio (V1 / V2) of the flow rate of the first fluid to the flow rate of the second fluid, the larger the diameter R1 of the hydrogel. Based on this relationship, the control device 900 can change the flow rate of at least one of the first fluid and the second fluid in a manner that makes the size of the actually formed hydrogel close to the size value of the hydrogel input by the user.

[0190] The method for manufacturing the hydrogel in the second embodiment can be carried out in substantially the same way as the manufacturing method described in the first embodiment. However, in the second embodiment, since the third flow path and its associated structure are not provided, the steps involving the third flow path and its associated structure described in the manufacturing method of the first embodiment can be omitted.

[0191] As described above, the present invention has been disclosed through implementation methods and embodiments, but it should not be construed as limiting the invention to the extent that the discussion and drawings constitute a part of this disclosure. Based on this disclosure, those skilled in the art will be able to recognize various alternative implementation methods, embodiments, and techniques. Therefore, the technical scope of the present invention is determined solely by the inventive specific matters of the appropriate claims based on the foregoing description.

[0192] This application claims priority based on Japanese Patent Application No. 2023-175600, filed on October 10, 2023, the entire contents of which are incorporated herein by reference.

Claims

1. A hydrogel manufacturing apparatus, characterized in that, have: The first flow path supplies the flow of the hydrogel precursor; The second flow path is for the flow of the gelling agent that gels the hydrogel precursor; The first confluence point of the first flow path and the second flow path; A storage container for storing hydrogels formed through contact between a hydrogel precursor and a gelling agent; A hydrogel flow path that at least provides closed communication between the receiving container and the first confluence point.

2. The hydrogel manufacturing apparatus according to claim 1, characterized in that, The storage container is made of a flexible container with an internal space that can expand and contract.

3. The hydrogel manufacturing apparatus according to claim 1 or 2, characterized in that, The hydrogel flow path is composed of a flexible tube.

4. The hydrogel manufacturing apparatus according to any one of claims 1 to 3, characterized in that, It has a first action unit that moves the liquid within the storage container.

5. The hydrogel manufacturing apparatus according to any one of claims 1 to 4, characterized in that, The storage container is a culture container for culturing cells.

6. The hydrogel manufacturing apparatus according to any one of claims 1 to 5, characterized in that, A pulsation suppression unit is provided on the upstream side of the first confluence point to suppress the pulsation of the hydrogel precursor and / or gelling agent.

7. The hydrogel manufacturing apparatus according to any one of claims 1 to 6, characterized in that, An antifoaming unit is provided upstream of the first confluence point, which removes bubbles from the solution containing the hydrogel precursor and / or gelling agent.

8. The hydrogel manufacturing apparatus according to claim 7, characterized in that, The defoaming unit has a gas receiving section located between the pump and the first confluence point.

9. The hydrogel manufacturing apparatus according to any one of claims 1 to 8, characterized in that, It has a pump for the flow of the hydrogel precursor and / or the gelling agent. The pump has the following properties: except during startup and shutdown, at a specific average flow rate value within the range of 0.1 mL to 1000 mL / min, the variation in flow rate is within 20% of that specific average flow rate value.

10. The hydrogel manufacturing apparatus according to any one of claims 1 to 9, characterized in that, It has a camera unit that captures the morphology of the hydrogel downstream of the first confluence point or at the first confluence point.

11. The hydrogel manufacturing apparatus according to claim 10, characterized in that, have: The analysis unit analyzes the morphology of the hydrogel captured by the camera unit; A control device that controls the flow rate of at least one of the hydrogel precursor and the gelling agent based on the results resolved by the analytical unit.

12. The hydrogel manufacturing apparatus according to claim 11, characterized in that, The analytical unit is configured to calculate the size of the formed hydrogel. The control device is configured to control the flow rate of at least one of the hydrogel precursor and the gelling agent based on the size of the hydrogel calculated by the analytical unit.

13. The hydrogel manufacturing apparatus according to claim 11 or 12, characterized in that, have: An input unit that sets the flow rate of at least one of the hydrogel precursor and the gelling agent; The storage unit stores the result parsed by the parsing unit together with the value of the flow rate set by the input unit.

14. The hydrogel manufacturing apparatus according to any one of claims 1 to 13, characterized in that, It has a third flow path for fluid flow. The third flow path is configured to merge with the first flow path at a second merging point upstream of the first merging point.

15. The hydrogel manufacturing apparatus according to claim 14, characterized in that, have: The third storage section stores the fluid; The second actuating unit moves the fluid within the third storage section.

16. The hydrogel manufacturing apparatus according to claim 15, characterized in that, have: The camera unit captures the morphology of the hydrogel at a point downstream of or at the first confluence point; The analysis unit analyzes the morphology of the hydrogel captured by the camera unit; A control device that controls the flow rate of at least one of the hydrogel precursor, the gelling agent, and the fluid based on the results resolved by the analysis unit.

17. The hydrogel manufacturing apparatus according to claim 16, characterized in that, The fluid contains cells. The analysis unit is configured to estimate the density of cells within the hydrogel based on image information captured by the camera unit.

18. The hydrogel manufacturing apparatus according to any one of claims 15 to 17, characterized in that, have: An input unit that sets the flow rate of at least one of the hydrogel precursor, the gelling agent, and the fluid; The storage unit stores the result parsed by the parsing unit together with the value of the flow rate set by the input unit.

19. The hydrogel manufacturing apparatus according to any one of claims 11-13 and 15-18, characterized in that, The analytical unit detects anomalies in at least one of the hydrogel, the first flow path, and the second flow path. The control device is configured to stop the delivery of the hydrogel precursor and the gelling agent when the abnormality is detected.

20. The hydrogel manufacturing apparatus according to any one of claims 1 to 19, characterized in that, It has a flow path component having the first flow path and the second flow path formed therein. The flow path component has an outlet that allows the hydrogel formed from the hydrogel precursor and the gelling agent to flow out. The distance from the first confluence point to the outlet is in the range of 3mm to 150mm.

21. The hydrogel manufacturing apparatus according to any one of claims 1 to 20, characterized in that, The hydrogel flow path is constructed through a tube made of rigid body.

22. A method for manufacturing a hydrogel, using the hydrogel manufacturing apparatus according to any one of claims 1 to 21, characterized in that, Includes the following steps: The hydrogel precursor is directed to flow into the first flow path; The gelling agent flows into the second flow path; The hydrogel precursor and the gelling agent are merged at the first confluence point to form a hydrogel. The formed hydrogel is introduced into the storage container through the hydrogel flow path.

23. The method for manufacturing hydrogel according to claim 22, characterized in that, The storage container is made of a flexible container with an internal space that can expand and contract. Before the hydrogel precursor and the gelling agent are dispensed, the internal space of the receiving container becomes capable of expansion.

24. The method for manufacturing hydrogel according to claim 22 or 23, characterized in that, This includes pre-feeding liquid to allow the liquid to flow through the hydrogel flow path before the formation of the hydrogel.

25. The method for manufacturing a hydrogel according to any one of claims 22 to 24, characterized in that, This includes checking for leaks in the flow paths included in the hydrogel manufacturing apparatus before forming the hydrogel.

Images