Hydrogel manufacturing apparatus and hydrogel manufacturing method

Abstract

The present invention provides a hydrogel manufacturing apparatus capable of suppressing contamination of impurities from formation of a hydrogel until usage thereof. A hydrogel manufacturing apparatus (100) comprises: 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 merging point (216) between the first flow path (212) and the second flow path (222); a housing container (400) for housing a hydrogel formed by contact between the hydrogel precursor and the gelling agent; and a hydrogel flow path (300) for connecting at least the housing container (400) and the first merging point (216) in a closed manner.

Description

Hydrogel manufacturing apparatus and hydrogel manufacturing method

[0001] The present invention relates to a hydrogel production apparatus and a hydrogel production method.

[0002] Patent Document 1 below discloses a method for producing hollow hydrogel fibers made of alginate polymer. In the method described in Patent Document 1, a hydrogel precursor is flowed around and along a core fluid, and a gelling agent is further flowed around the hydrogel precursor. As a result, the hydrogel precursor gels, forming a long, thin fibrous hydrogel.

[0003] International Publication No. 2011 / 046105

[0004] In Patent Document 1, the hydrogel is formed in a container suitable for forming the hydrogel. The formed hydrogel is usually transferred to another container suitable for use when the hydrogel is to be used. Therefore, there is a risk of impurities being mixed into the hydrogel or a solution containing the hydrogel during transportation of the hydrogel.

[0005] Therefore, there is a demand for a hydrogel production apparatus and a hydrogel production method that can prevent impurities from being mixed in from the time of hydrogel formation until the time of use.

[0006] A hydrogel manufacturing apparatus according to one embodiment includes a first flow path for flowing a hydrogel precursor, a second flow path for flowing a gelling agent that gels the hydrogel precursor, a first confluence of the first flow path and the second flow path, a storage container for storing a hydrogel formed by contact of the hydrogel precursor with the gelling agent, and a hydrogel flow path that provides closed communication between at least the storage container and the first confluence.

[0007] A hydrogel manufacturing method according to one embodiment is a method using the above-described hydrogel manufacturing apparatus, and includes flowing a hydrogel precursor into the first flow path, flowing a gelling agent into the second flow path, causing the hydrogel precursor and gelling agent to merge at the first junction to form a hydrogel, and introducing the formed hydrogel into the storage container through the hydrogel flow path.

[0008] 11 is a schematic diagram of a hydrogel-producing apparatus according to a first embodiment; FIG. 12 is a schematic diagram for explaining the structure of the flow channels of the hydrogel-producing apparatus according to the first embodiment; FIG. 13 is a block diagram of the hydrogel-producing apparatus according to the first embodiment; FIG. 14 is a perspective view showing an example of the structure of a hydrogel formed in the first embodiment; FIG. 15 is a cross-sectional view of the hydrogel shown in FIG. 4; FIG. 16 is a diagram showing an example of data stored in a storage unit according to the first embodiment; FIG. 17 is a schematic diagram for explaining the state of each introduction channel at the initial stage of a leak test; FIG. 18 is a schematic diagram for explaining the state of each introduction channel at a stage subsequent to FIG. 7; FIG. 19 is a schematic diagram for explaining the state of each introduction channel at a stage subsequent to FIG. 8; FIG. 19 is a schematic diagram for explaining the state of each introduction channel at a preliminary liquid transfer (pre-liquid transfer) stage; FIG. 20 is a schematic diagram for explaining the state of each introduction channel at a preparation stage for a pulsation suppression means and / or a debubbling means; FIG. 21 is a schematic diagram for explaining the state of each introduction channel at a stage subsequent to FIG. 22; 16 is a perspective view showing an example of the structure of a hydrogel formed in the second embodiment. FIG. 17 is a cross-sectional view of the hydrogel shown in FIG. 16. FIG. 18 is a diagram showing an example of data stored in a storage unit in the second embodiment.

[0009] Hereinafter, embodiments will be described with reference to the drawings. In the following drawings, the same or similar parts are denoted by the same or similar reference numerals. However, it should be noted that the drawings are schematic and the ratios of the dimensions may differ from those of the actual parts.

[0010] [First Embodiment] Fig. 1 is a schematic diagram of a hydrogel-producing apparatus according to a first embodiment. Fig. 2 is a schematic diagram for explaining the structure of a flow path of the hydrogel-producing apparatus according to the first embodiment. Fig. 3 is a block diagram of the hydrogel-producing apparatus according to the first embodiment. It should be noted that the structure of the flow path is shown in a simplified manner or is not shown at all in Fig. 1. The hydrogel-producing apparatus 100 may include a first reservoir 102, a second reservoir 104, a third reservoir 106, and a flow path component 200.

[0011] The first reservoir 102 stores a first fluid. The first fluid is a hydrogel precursor (hereinafter the same). The hydrogel precursor is preferably a solution (including a sol) containing, for example, alginate or agarose. More specifically, the first fluid may be a solution containing, for example, sodium alginate, potassium alginate, ammonium alginate, or a combination thereof. The alginate may be a natural extract or a chemically modified alginate. Examples of chemically modified alginates include methacrylate-modified alginate. The first fluid may also be a mixture of the aforementioned alginate with agar, agarose, polyethylene glycol (PEG), polylactic acid (PLA), nanocellulose, or the like. The first fluid may contain an excipient and / or a thickener in addition to the hydrogel precursor.

[0012] The second reservoir 104 stores a second fluid (gelling agent) that gels the first fluid (hydrogel precursor) upon contact with the first fluid. When the first fluid is the alginate polymer material, the second fluid may be a solution containing multivalent cations. Examples of such solutions include solutions containing calcium ions or barium ions, such as calcium chloride or barium chloride. The alginate polymer material forms an alginate gel by being crosslinked by the multivalent cations. The second fluid may contain an excipient and / or a thickener in addition to the gelling agent.

[0013] The third reservoir 106 stores a third fluid. The third fluid may be a sol, a gel, or a liquid (including a suspension). Preferably, the third fluid may be a gel or a liquid. The type of gel or liquid constituting the third fluid is not particularly limited. These gels or liquids may be, for example, an alginate solution, a chitosan gel, a collagen gel, gelatin, a peptide gel, a fibrin gel, a laminin gel, nanocellulose, pullulan, dextran, a culture medium, or a mixture thereof. The third fluid may contain an excipient and / or a thickener.

[0014] The hydrogel manufacturing apparatus 100 may have a second operating unit 107 that moves the fluid in the third reservoir 106. When the fluid in the third reservoir 106 contains suspended particles, the second operating unit 107 may be, for example, a stirrer that stirs the third fluid in the third reservoir 106, or a shaking unit that shakes the third reservoir 106 itself.

[0015] If the third fluid contains, for example, suspended particles, the action of second operating unit 107 uniformly disperses the suspended particles in the third fluid in third reservoir 106. As a result, when a hydrogel is formed as described below, the suspended particles are uniformly contained in the hydrogel.

[0016] The flow path forming member 200 is a member including flow paths through which the first fluid, the second fluid, and the third fluid flow. The flow path forming member 200 is preferably made of a non-flexible member. The flow path forming member 200 may be made of, for example, a metal or synthetic resin member.

[0017] 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 reservoir 102. The second inlet 220 is an inlet for a second fluid and is in fluid communication with the second reservoir 104. The third inlet 230 is an inlet for a third fluid and is in fluid communication with the third reservoir 106.

[0018] The flow path forming member 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 forming member 200.

[0019] The first flow path 212 is a flow path for flowing the hydrogel precursor, and may be defined by a flow path that runs from the first inlet 210 to the outlet 240 via a first junction 216 (described later). In this embodiment, the first flow path 212 runs from the first inlet 210 to the outlet 240 via a second junction 226 (described later) and the first junction 216. The first fluid runs from the first inlet 210 to the outlet 240 via the first flow path 212.

[0020] The second flow path 222 may be defined by a flow path from the second inlet 220 to the first junction 216. The second flow path 222 is a flow path for flowing a gelling agent. The first junction 216 is a junction 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 junction 216 into the first flow path 212 and then to the outlet 240.

[0021] The third flow path 232 may be defined by a flow path from the third inlet 230 to the second junction 226. The second junction 226 is a junction point between the first flow path 212 and the third flow path 232. The second junction 226 may be located upstream of the first junction 216 in the direction of flow 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 junction 226, which is upstream of the first junction 216. The third fluid is introduced from the third inlet 230 through the third flow path 232, the second junction 226, and the first junction 216 into the first flow path 212, and then to the outlet 240.

[0022] The second flow path 222 is configured to merge the second fluid (gelling agent) around the first fluid in the first flow path 212 at the first junction 216. This causes the second fluid to flow around the first fluid in the same direction as the flow of the first fluid. That is, the second fluid surrounds the first fluid (hydrogel precursor) in a cross section perpendicular to the flow of the first fluid.

[0023] A hydrogel is formed by contacting the first fluid (hydrogel precursor) and the second fluid (gelling agent) at first junction 216. The hydrogel flows downstream from first junction 216 toward outlet 240.

[0024] Preferably, the first fluid and the second fluid flow as laminar flows through the first flow path 212 and the second flow path 222, respectively. This allows the second fluid to neatly surround the first fluid in a cross section perpendicular to the flow direction of the first fluid without substantially mixing with the first fluid. This makes it easier to form a hydrogel with a regular shape.

[0025] In the first embodiment, the first flow path 212 is configured to merge the first fluid around the third fluid that has flowed into the first flow path 212 at the second junction 226. As a result, the first fluid flows around the third fluid in the direction of the flow of the third fluid. That is, the first fluid surrounds the third fluid in a cross section perpendicular to the direction of the flow of the third fluid. That is, the first fluid flows while maintaining a tubular shape surrounding the third fluid, and then comes into contact with the second fluid at the first junction 216 and becomes a hydrogel. As a result, a hydrogel having a tubular shape can be formed.

[0026] Preferably, the first fluid and the third fluid flow as laminar flows through the first flow path 212 and the third flow path 232, respectively. This allows the first fluid to neatly surround the third fluid without substantially mixing with the third fluid in a cross section perpendicular to the flow of the third fluid. This makes it easier to form a tubular hydrogel with a regular shape (see also FIG. 4 ).

[0027] As described above, the flow path forming member 200 is preferably made of a non-flexible material. In this case, the first flow path 212, the second flow path 222, and the third flow path 232 are less likely to deform due to external forces, and therefore laminar flows of the first fluid, the second fluid, and / or the third fluid are more likely to be stably formed in the first flow path 212, the second flow path 222, and the third flow path 232, respectively. Therefore, a hydrogel having a more regular tubular shape is more likely to be produced.

[0028] The sizes, such as the channel diameters, of the first channel 212, the second channel 222, and the third channel 232 can be appropriately designed depending on the size of each part of the hydrogel to be manufactured. To form an elongated or small hydrogel, the channel diameters of the first channel 212, the second channel 222, and the third channel 232 may be small. The channel diameters (inner diameters) of the first channel 212, the second channel 222, and the third channel 232 may be, for example, 5 mm or less or 3 mm or less. Furthermore, the channel diameter (inner diameter) at the outlet 240 may be, for example, 30 mm or less, 10 mm or less, 5 mm or less, or 3 mm or less.

[0029] The distance from the first junction 216 to the outlet 240 may 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 junction 216 to the outlet 240 is long, the hydrogel flows out of the outlet 240 after the shape of the hydrogel has stabilized in the flow path forming member 200. This makes it possible to prevent the hydrogel from collapsing in the hydrogel flow path 300. Furthermore, the shorter the distance from the first junction 216 to the outlet 240, the smaller the size of the flow path forming member 200 can be.

[0030] The hydrogel manufacturing apparatus 100 may have a housing 120 and a support part 140 that supports the flow path forming member 200. The support part 140 is provided in the housing 120 and fixes the flow path forming member 200 to the housing 120. This makes it possible to suppress vibration of the flow path forming member 200 during the production of the hydrogel.

[0031] The hydrogel-producing apparatus 100 may have a first inlet channel 132 that fluidly connects the first reservoir 102 and the first flow channel 212 of the flow channel forming member 200, a second inlet channel 134 that fluidly connects the second reservoir 104 and the second flow channel 222 of the flow channel forming member 200, and a third inlet channel 136 that fluidly connects the third reservoir 106 and the third flow channel 232 of the flow channel forming member 200. These inlet channels 132, 134, and 136 may be formed, for example, in a non-flexible member or in a flexible tube. These inlet channels 132, 134, and 136 may be attached to the housing 120 or may be provided within the housing 120.

[0032] The hydrogel manufacturing apparatus 100 may include a first pump 112 that delivers a first fluid, a second pump 114 that delivers a second fluid, and a third pump 116 that delivers a third fluid. The first pump 112, the second pump 114, and the third pump 116 may be configured to be able to adjust the flow rates and flow velocities of the first fluid, the second fluid, and the third fluid, respectively.

[0033] The flow rate settings of the first pump 112, the second pump 114, and the third pump 116 may be configured to be adjustable by the user, or may be automatically adjusted by a preset program.

[0034] There are no particular limitations 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 may be pumps that reduce pulsation of the liquid they pump. The first pump 112, the second pump 114, and the third pump 116 may be pumps that have performance such that, at a specific average flow rate value, for example, a specific average flow rate value within a range of 0.1 mL to 1000 mL / min, the amount of flow rate fluctuation is, for example, within 20%, preferably within 10%, more preferably within 5%, and even more preferably within 2% of the specific average flow rate value, except when the pumps are started and stopped.

[0035] The first inlet path 132 may include a first inlet valve 162 between the first reservoir 102 and a first pulsation suppression means 610 and / or a first debubbling means 710 (described later). When the first pump 112 is operated with the first inlet valve 162 open, the first fluid flows from the first reservoir 102 toward the first inlet path 132. The cross-sectional area of ​​the first inlet path 132 is preferably larger than the cross-sectional areas of the second inlet path 134 and / or the third inlet path 136. The first fluid flowing through the first inlet path 132 is a hydrogel precursor and has a relatively high viscosity. Therefore, a large cross-sectional area of ​​the first inlet path 132 makes it easier to flow a first fluid with a high viscosity without excessively increasing the pumping pressure of the first pump 112. From this perspective, the first inlet path 132 may be a single path or may be branched into multiple paths arranged in parallel. In this case, the cross-sectional area of ​​the first inlet passage 132 is defined as the sum of the cross-sectional areas of the multiple passages.

[0036] The second inlet passage 134 may have a second inlet valve 164 between the second reservoir 104 and a second pulsation suppression means 620 and / or a second defoaming means 720, which will be described later. When the second pump 114 is operated with the second inlet valve 164 open, the second fluid flows from the second reservoir 104 toward the second inlet passage 134.

[0037] The third inlet passage 136 may have a third inlet valve 166 between the third reservoir 106 and a third pulsation suppression means 630 and / or a third bubble removal means 730, which will be described later. When the third pump 116 is operated with the third inlet valve 166 open, the third fluid flows from the third reservoir 106 toward the third inlet passage 136.

[0038] The hydrogel-manufacturing apparatus 100 may have a cleaning mechanism that cleans at least a portion of the first flow path 212, the second flow path 222, and the third flow path 232. In the first embodiment, the hydrogel-manufacturing apparatus 100 may have a cleaning container 108 that stores a cleaning liquid. The cleaning liquid is preferably water, pure water, physiological saline, or the like. The second pump 114 may serve not only as a pump for delivering the second fluid but also as a pump for delivering the cleaning liquid. Alternatively, a pump dedicated to delivering the cleaning liquid (a cleaning pump) may be provided. In this case, the cleaning pump may be provided in the cleaning flow path 138 through which substantially only the cleaning liquid flows.

[0039] The cleaning container 108 is preferably fluidly connected to 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. This allows the cleaning liquid to reach the outlet 240 through the cleaning flow path 138, the second inlet path 134, the second flow path 222, and the first junction 216. Alternatively, the cleaning container 108 may merge with the first inlet path 132. Alternatively, 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 and the cleaning flow path 138 connected to the first inlet path 132 may be provided separately from the cleaning container 108 and the cleaning flow path 138 connected to the second inlet path 134.

[0040] The cleaning flow path 138 may have a cleaning valve 168. When the cleaning pump and / or the second pump 114 is operated with the cleaning valve 168 open, water flows from the cleaning container 108 toward the cleaning flow path 138 and the second inlet path 134.

[0041] The hydrogel-producing apparatus 100 may have a first air inlet passage 152, a second air inlet passage 154, and a third air inlet passage 156 that introduce gas into the first inlet passage 132, the second inlet passage 134, and the third inlet passage 136, respectively. The first air inlet passage 152, the second air inlet passage 154, and the third air inlet passage 156 are connected to the first inlet passage 132, the second inlet passage 134, and the third inlet passage 136, respectively. The first air inlet passage 152, the second air inlet passage 154, and the third air inlet passage 156 are used to check for leaks in the first inlet passage 132, the second inlet passage 134, and the third inlet passage 136.

[0042] The first inlet path 132, the second inlet path 134, and the third inlet path 136 may have air valves 182, 184, and 186, respectively. By opening and closing the air valves 182, 184, and 186, it is possible to control whether or not gas is introduced into the first inlet path 132, the second inlet path 134, and the third inlet path 136.

[0043] 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 into the first inlet passage 132 or to introduce 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 into the third inlet passage 136 or to introduce gas into the third inlet passage 136.

[0044] In addition, 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 into the second inlet passage 134, the cleaning liquid into the second inlet passage 134, or the gas into the second inlet passage 134.

[0045] The first inlet passage 132 may have a fourth inlet valve 172 downstream of the junction of the first inlet passage 132 and the first air inlet passage 152. The second inlet passage 134 may have a fifth inlet valve 174 downstream of the junction of the second inlet passage 134 and the second air inlet passage 154. The third inlet passage 136 may have a sixth inlet valve 176 downstream of the junction of the third inlet passage 136 and the third air inlet passage 156.

[0046] Preferably, the fourth introduction valve 172 may be provided between the flow path forming member 200 and a first pulsation suppression means 610 and / or a first defoaming means 710, which will be described later. Preferably, the fifth introduction valve 174 may be provided between the flow path forming member 200 and a second pulsation suppression means 620 and / or a second defoaming means 720, which will be described later. Preferably, the sixth introduction valve 176 may be provided between the flow path forming member 200 and a third pulsation suppression means 630 and / or a third defoaming means 730, which will be described later.

[0047] The fourth inlet valve 172, the fifth inlet valve 174 and the sixth inlet valve 176 can be used to prevent fluid from flowing back into other inlet paths through the flow path forming member 200 when fluid is flowing into one of the first inlet path 132, the second inlet path 134 and the third inlet path 136.

[0048] The hydrogel manufacturing apparatus 100 may include a hydrogel flow path 300 and a storage container 400. The storage container 400 is a container that stores a hydrogel formed by contact between a first fluid (hydrogel precursor) and a second fluid (gelling agent). The storage container 400 is not particularly limited, but may be a container that is suitable for the usage environment and / or purpose of the hydrogel formed in the flow path forming member 200, more specifically, a container that is designed in advance according to the usage environment and / or purpose of use.

[0049] The hydrogel flow channel 300 is a flow channel that provides closed communication at least between the storage container 400 and the first junction 216. Preferably, the hydrogel flow channel 300 provides closed communication between the outlet 240 of the flow channel forming member 200 and the storage container 400. Here, the hydrogel flow channel 300 is preferably configured to provide airtight and / or liquidtight communication from the first junction 216 to the storage container 400. This allows the hydrogel formed by contact between the first fluid (hydrogel precursor) and the second fluid (gelling agent) to be transported to the storage container 400, which is separated from the flow channel forming member 200, in an airtight and / or liquidtight state. This prevents impurities from being mixed into the formed hydrogel or the fluid flowing with the hydrogel.

[0050] The hydrogel flow path 300 may have a first end 310 that can be attached to the outlet 240 of the flow path forming member 200, and a second end 320 that can be detached from the inlet 410 of the storage container 400. This makes it easier to communicate the outlet 240 of the flow path forming member 200 with storage containers 400 that have different designs depending on the usage environment and / or purpose of the hydrogel.

[0051] The hydrogel flow path 300 may have a length of, for example, 0.1 m to 10 m, 0.2 m to 8 m, or 0.4 m to 5 m, without any particular limitation, which allows the hydrogel to be transferred in a closed system from the flow path forming member 200 to the storage container 400, which is relatively far away.

[0052] The hydrogel channel 300 may be formed of a flexible tube or a rigid tube. When the hydrogel channel 300 is formed of a rigid tube, the shape of the hydrogel channel 300 is likely to be stably maintained.

[0053] On the other hand, when the hydrogel flow path 300 is formed by a flexible tube, even if the positional relationship between the flow path forming member 200 and the storage container 400 changes, the hydrogel flow path 300 can maintain a closed communication state between the storage container 400 and the first junction 216 due to the curvature of the tube. When a storage container 400 with a different design is used depending on the usage environment and / or purpose of the hydrogel, restrictions may be imposed on the installation position of the storage container 400. Even if the installation position of the storage container 400 changes due to such restrictions, the hydrogel flow path 300 formed by the flexible tube can maintain a closed communication state between the storage container 400 and the first junction 216.

[0054] The inner diameter (diameter of the internal space) of the hydrogel flow channel 300 is not particularly limited, and may 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 channel diameter (inner diameter) at the outlet 240 of the flow channel forming member 200. Since the hydrogel formed in the flow channel forming member 200 passes through it, the inner diameter of the hydrogel flow channel 300 is desirably 1 time or more the inner diameter of the outlet 240. Furthermore, in order to prevent the tubular hydrogel formed in the flow channel forming member 200 from bending in the hydrogel flow channel 300, it is desirable that the upper limit of the hydrogel flow channel 300 be equal to or less than the desired value described above.

[0055] In the illustrated embodiment, the hydrogel channel 300 is formed by a single tube, but alternatively, the hydrogel channel 300 may be formed by connecting a plurality of tubes in series.

[0056] There are no particular limitations on the storage container 400 as long as it is a container suitable for the environment and / or purpose of use of the hydrogel. Preferably, the storage container 400 is configured as a flexible container having an expandable and contractible internal space.

[0057] If the internal space of the storage container 400 is not expandable and contractible, it is desirable to evacuate the gas in the internal space of the storage container 400 to prevent the pressure in the internal space of the storage container 400 from increasing when the hydrogel formed by the flow path forming member 200 is flowed into the storage container 400.

[0058] On the other hand, if the storage container 400 is configured as a flexible container having an expandable and contractible internal space, the hydrogel can be introduced into the storage container 400 with the internal space of the storage container 400 being depressed. In this case, it is not necessary to exhaust the gas in the internal space of the storage container 400 while the hydrogel formed by the flow path forming member 200 is being introduced into the storage container 400. Therefore, the possibility of impurities being mixed into the storage container 400 can be further reduced.

[0059] The hydrogel-producing apparatus 100 may have a first operating unit 500 that moves the liquid in the storage container 400. The first operating unit 500 may be, for example, a stirrer that stirs the liquid in the storage container 400, or a shaking unit that shakes the storage container 400 itself.

[0060] Even if the first operating unit 500 is a rocking unit that rocks the storage container 400 itself, if the hydrogel flow path 300 is constructed from a flexible tube, there is an advantage that the influence of the rocking of the storage container 400 is less likely to be transmitted to the flow path forming member 200.

[0061] The storage container 400 may have an outlet port 420 for discharging the liquid in the internal space, and an inlet port 430 for introducing a liquid different from the liquid used in forming the hydrogel into the internal space. By using the outlet port 420 and the inlet port 430, the liquid accumulated in the internal space of the storage container 400 during the formation of the hydrogel can be removed and / or replaced.

[0062] 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 in the inner space of the formed tubular hydrogel. When the first fluid contains cells, the cells are embedded in the formed tubular hydrogel. In these cases, the storage container 400 may be, for example, a culture container for culturing cells. In this case, the introduction port 430 may be a port for introducing a culture medium into the storage container 400.

[0063] The type of cells is not particularly limited. Such cells may be, for example, pluripotent ES cells or iPS cells, various pluripotent stem cells (hematopoietic stem cells, neural stem cells, mesenchymal stem cells, etc.), or unipotent stem cells (hepatic stem cells, germline stem cells, etc.). Alternatively, the cells contained in the first fluid may be various differentiated cells, such as muscle cells such as skeletal muscle cells and cardiac muscle cells, nerve cells such as cerebral cortex cells, fibroblasts, epithelial cells, hepatocytes, pancreatic beta cells, skin cells, etc. Furthermore, it should be noted that the term "cell" is not limited to a single cell, but also includes microorganisms such as bacteria, as well as cellular tissues consisting of multiple cells.

[0064] The first fluid and / or the third fluid may contain various growth factors suitable for cell culture, cell maintenance and proliferation, or cell function 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.

[0065] The hydrogel-producing apparatus 100 may have a first pulsation suppression means 610, a second pulsation suppression means 620, and / or a third pulsation suppression means 630. The first pulsation suppression means 610 is a means for suppressing pulsation of the first fluid generated by the first pump 112. The second pulsation suppression means 620 is a means for suppressing pulsation of the second fluid generated by the second pump 114. The third pulsation suppression means 630 is a means for suppressing pulsation of the third fluid generated by the third pump 116.

[0066] The first pulsation suppression means 610 may be provided upstream of the first junction 216, preferably upstream of the second junction 226, and more preferably upstream of the flow path forming member 200. The second pulsation suppression means 620 may be provided upstream of the first junction 216, preferably upstream of the flow path forming member 200. The third pulsation suppression means 630 may be provided upstream of the second junction 226, and preferably upstream of the flow path forming member 200.

[0067] The pulsation suppressing means 610, 620, 630 may include any means for suppressing pulsation. By suppressing the pulsation of the first fluid, the second fluid, and / or the third fluid, each of the first fluid, the second fluid, and / or the third fluid hardly mixes with the other fluids at the first junction 216 and / or the second junction 226, and is likely to form a clean laminar flow. This makes it possible to suppress variation in the shape of the hydrogel that is finally formed.

[0068] The hydrogel-producing apparatus 100 may have a first defoaming means 710, a second defoaming means 720, and / or a third defoaming means 730. The first defoaming means 710 is a means for removing gas (bubbles) from a first fluid. The second defoaming means 720 is a means for removing gas (bubbles) from a second fluid. The third defoaming means 730 is a means for removing gas (bubbles) from a third fluid.

[0069] The first defoaming means 710 may be provided upstream of the first junction 216, preferably upstream of the second junction 226, and more preferably upstream of the flow path forming member 200. The second defoaming means 720 may be provided upstream of the first junction 216, preferably upstream of the flow path forming member 200. The third defoaming means 730 may be provided upstream of the second junction 226, and preferably upstream of the flow path forming member 200.

[0070] By removing bubbles from the first fluid, the second fluid, and / or the third fluid, each of the first fluid, the second fluid, and / or the third fluid is likely to form a clean laminar flow at the first junction 216 and / or the second junction 226. This makes it possible to suppress variation in the shape of the hydrogel that is finally formed.

[0071] The first pulsation suppression means 610 and the first bubble removing means 710 may be separate means or the same means. When the first pulsation suppression means 610 and the first bubble removing means 710 are the same means, a single means (unit) can both suppress the pulsation of the first fluid and remove bubbles from the first fluid. Similarly, the second pulsation suppression means 620 and the second bubble removing means 720 may be separate means or the same means. Furthermore, the third pulsation suppression means 630 and the third bubble removing means 730 may be separate means or the same means.

[0072] In the illustrated embodiment, the first pulsation suppression means 610 and the first bubble removing means 710 are configured by the same means, i.e., a common unit. Similarly, the second pulsation suppression means 620 and the second bubble removing means 720 are configured by the same means, i.e., a common unit. Furthermore, the third pulsation suppression means 630 and the third bubble removing means 730 are configured by the same means, i.e., a common unit.

[0073] In the illustrated example, the first pulsation suppression means 610 and the first defoaming means 710 are located between the first pump 112 and the first junction 216, preferably between the first pump 112 and the flow path forming member 200. The first pulsation suppression means 610 and the first defoaming means 710 have a storage portion 612 capable of holding gas.

[0074] The storage section 612 communicates with the first inlet path 132 and may be sealed at a location other than the first inlet path 132. The first fluid sent from the first pump 112 to the storage section 612 via the first inlet path 132 is temporarily stored in the storage section 612. Air bubbles in the first fluid temporarily stored in the storage section 612 accumulate within the storage section 612. The first inlet path 132 communicates with the storage section 612 at a portion below the storage section 612. Therefore, air bubbles stored in the storage section 612 are less likely to mix into the flow path forming member 200.

[0075] Furthermore, as the first fluid accumulates in the storage portion 612 and the pressure inside the storage portion 612 increases, the first fluid is sent from the storage portion 612 toward the flow path forming member 200. Because the pressure fluctuation inside the storage portion 612 is smaller than the pulsation caused by the first pump 112, the first fluid is sent toward the flow path forming member 200 in a state in which the pulsation of the first fluid caused by the influence of the first pump 112 is suppressed.

[0076] The first pulsation suppression means 610 and the first debubbling means 710 preferably have a pressure sensor 616 that measures the pressure inside the storage section 612. After the pressure detected by the pressure sensor 616 reaches a desired value, the fourth introduction valve 172 can be opened to appropriately send the first fluid toward the flow path forming member 200.

[0077] In the illustrated example, the second pulsation suppression means 620 and the second defoaming means 720 are located between the second pump 122 and the first junction 216, preferably between the second pump 122 and the flow path forming member 200. The structures of the second pulsation suppression means 620 and the second defoaming means 720 are similar to those of the first pulsation suppression means 610 and the first defoaming means 710, and therefore a description thereof will be omitted.

[0078] In the illustrated example, the third pulsation suppression means 630 and the third defoaming means 730 are located between the third pump 116 and the second junction 226, preferably between the third pump 116 and the flow path forming member 200. The structures of the third pulsation suppression means 630 and the third defoaming means 730 are similar to those of the first pulsation suppression means 610 and the first defoaming means 710, and therefore a description thereof will be omitted.

[0079] The hydrogel-producing apparatus 100 may include an imaging unit 800. The imaging unit 800 may be configured to acquire the morphology of the hydrogel downstream of the first junction 216 or at the first junction 216. Preferably, the imaging unit 800 may be configured to acquire the morphology of the hydrogel downstream of the outlet 240 of the flow channel forming member 200, i.e., in the hydrogel flow channel 300.

[0080] The imaging unit 800 captures the morphology of the hydrogel as an image (including a still image or a video image). The image captured by the imaging unit 800 is preferably sent to a control device 900, which will be described later.

[0081] Fig. 4 is a perspective view showing an example of the structure of the hydrogel formed in the first embodiment. Fig. 5 is a cross-sectional view of the hydrogel shown in Fig. 4. As shown in Fig. 4, the hydrogel 10 is formed in a long, tubular shape. Hereinafter, the tubular hydrogel may be referred to as a "shell 14." Furthermore, the inner portion of the tubular hydrogel, i.e., the portion formed by the first fluid, may be referred to as a "core 12."

[0082] If the storage container 400 is constructed as a flexible container having an expandable and contractible internal space, it is preferable that, during the production of the hydrogel, the internal space of the storage container 400 is made expandable as described above before the first fluid, second fluid, and third fluid are delivered.

[0083] The hydrogel-producing apparatus 100 may include a control device 900 that controls each of the components constituting the apparatus. The control device 900 may include an input unit 910, an analysis unit 920, a command unit 930, and a storage unit 940.

[0084] The control device 900 may, for example, control the first pump 112, the second pump 114, and the third pump 116, or control the opening and closing of the first introduction valve 162, the second introduction valve 164, the third introduction valve 166, the fourth introduction valve 172, the fifth introduction valve 174, the sixth introduction valve 176, the cleaning valve 168, and / or the air valves 182, 184, and 186.

[0085] The control device 900 may include a CPU (Central Processing Unit), a ROM (Read Only Memory), and a RAM (Random Access Memory). The CPU is a calculation device. An example of the details of the control by the control device 900 will be described in detail below. The ROM stores programs that realize various processes by the CPU. Such programs may be, for example, programs for executing the various controls described in the above embodiments. The RAM stores data necessary for various processes by the CPU.

[0086] The input unit 910 accepts input from a user who uses the hydrogel manufacturing apparatus 100. The input unit 910 accepts input from an input device such as a keyboard, a mouse, or a touch panel.

[0087] In one example, the input unit 910 may be configured to be able to accept set values ​​for the flow rate of the first fluid path, the flow rate of the second fluid path, and the flow rate of the third fluid path. In other words, the user can input the flow rate of the first fluid, the flow rate of the second fluid, and the flow rate of the third fluid from the input device.

[0088] It is preferable that the input unit 910 is configured to be able to accept each 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, but instead, the input unit 910 may be configured to be able to accept 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.

[0089] The command unit 930 sends commands to operate the first pump 112, the second pump 114, and the third pump 116. When the command unit 930 receives set values ​​of the flow rates of the first fluid, the second fluid, and the third fluid from the input unit 910, the command unit 930 operates the first pump 112, the second pump 114, and the third pump 116 based on the input set values ​​of the flow rates. This makes it possible to set and / or change the flow rates of the first fluid, the second fluid, and the third fluid in response to a request for set values ​​of the flow rates from the user.

[0090] The flow rates of the first fluid, the second fluid, and the third fluid affect the size of the tubular hydrogel formed. Specifically, the flow rates V1, V2, and V3 of the first fluid affect the shell diameter (total diameter of the hydrogel) R1, the core diameter R2, and the ratio (S3 / S1) of the core cross-sectional area S3 to the shell cross-sectional area S1 of the tubular hydrogel formed (see also FIG. 5 ). Here, the cross-sectional area is the area of ​​a cross section perpendicular to the longitudinal direction of the tube. For example, the flow rates of the first fluid, the second fluid, and the third fluid have the relationships shown in Table 1 below with the shell diameter R1, the core diameter R2, and the ratio (S3 / S1) of the core cross-sectional area S3 to the shell cross-sectional area S1 of the tubular hydrogel. Note that in Table 1 below, the "reference" is merely a reference for comparison with Examples 1 to 3.

[0091] (Table 1)

[0092] More specifically, when the flow rate of the second fluid is increased without changing the flow rates of the first and third fluids, both the shell diameter R1 and the core diameter R2 decrease (see comparison between the standard and Example 1 in Table 1). However, the ratio of the core cross-sectional area S3 to the shell cross-sectional area S1 (S3 / S1) does not change significantly. Furthermore, when the flow rate of the first fluid is increased without changing the flow rates of the second and third fluids, the shell diameter R1 increases, and the ratio of the core cross-sectional area S3 to the shell cross-sectional area S1 (S3 / S1) decreases (see comparison between the standard and Example 2 in Table 1). Furthermore, when the flow rate of the third fluid is increased without changing the flow rates of the first and second fluids, the shell diameter R1 and the core diameter R2 increase, and the ratio of the core cross-sectional area S3 to the shell cross-sectional area S1 (S3 / S1) also increases (see comparison between the standard and Example 3 in Table 1).

[0093] Therefore, by appropriately setting the flow rate V1 of the first fluid, the flow rate V2 of the second fluid, and the flow rate V3 of the third fluid, the user can appropriately adjust the shell diameter R1, the core diameter R2, 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 that is formed.

[0094] The control device 900 may acquire data of the image of the hydrogel acquired by the imaging device 800. The analysis unit 920 may be configured to analyze the morphology of the hydrogel imaged by the imaging unit 800.

[0095] The analysis unit 920 analyzes the image of the hydrogel transferred into the image by a known image analysis process. Preferably, the analysis unit 920 calculates a value 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.

[0096] The storage unit 940 may store the results of the analysis performed by the analysis unit 920 together with the set values ​​of the flow rates set by the input unit 910. The value relating to the size of the hydrogel calculated by the analysis unit 920 is preferably stored in the storage unit 940 in association with information relating to the flow rate V1 of the first fluid, the flow rate V2 of the second fluid, and the flow rate V3 of the third fluid during the production of the hydrogel.

[0097] 6 is a diagram showing an example of data stored in the storage unit in the first embodiment. As shown in Fig. 6, 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 may be stored in the storage unit 940 in association with the flow velocity V1 of the first fluid, the flow velocity V2 of the second fluid, and the flow velocity V3 of the third fluid during the production of the hydrogel.

[0098] The information on the size and flow rate of the hydrogel stored in the storage unit 940 may be configured so that the user can check it in response to a command from the user. For example, the information shown in Fig. 6 may be displayed on a display device 980 such as a monitor provided in the hydrogel-producing apparatus 100. In this case, when producing a new hydrogel, the user can easily set an appropriate flow rate value based on size data of previously formed hydrogels.

[0099] In the above description, the input unit 910 receives information about the flow rates of the first flow path, the second flow path, and the third flow path. However, the input unit 910 may also receive information about the size of the hydrogel to be formed. For example, the input unit 910 may receive information about the shell diameter R1 and the core diameter R2 of the hydrogel to be formed.

[0100] When the control device 900 receives information about the size of the hydrogel to be formed, such as a shell diameter R1 and a core diameter R2, input by the user, the control device 900 automatically determines the flow rate V1 of the first fluid, the flow rate V2 of the second fluid, and the flow rate V3 of the third fluid based on the information about the size of the hydrogel. The flow rate V1 of the first fluid, the flow rate V2 of the second fluid, and the flow rate V3 of the third fluid can be obtained, for example, from information about the size of hydrogels previously manufactured. Specifically, the control device 900 can determine the flow rate V1 of the first fluid, the flow rate V2 of the second fluid, and the flow rate V3 of the third fluid based on past data stored in the memory unit 940 (see FIG. 6 ), i.e., the relationship between the flow rate V1 of the first fluid, the flow rate V2 of the second fluid, and the flow rate V3 of the third fluid and the size (diameters R1 and R2) of the hydrogel.

[0101] In this case, the command unit 930 of the control device 900 controls the flow rates of the first fluid, the second fluid, and the third fluid, i.e., the first pump 112, the second pump 114, and the third pump 116, according to the determined flow rate values ​​V1, V2, and V3.

[0102] Furthermore, the control device 900 may be configured to control (feedback control) the flow rate of at least one of the first fluid (hydrogel precursor), the second fluid (gelator), and the third fluid based on the results of analysis by the analysis unit 920. Specifically, as described above, the analysis unit 920 calculates information about the size of the actually formed hydrogel (e.g., various diameters R1 and R2) based on an image of the formed hydrogel. Furthermore, the analysis unit 920 calculates a deviation between the information about the actually formed hydrogel size (e.g., various diameters R1 and R2) and the information about the hydrogel size received by the input unit 910. The command unit 930 may control, i.e., change, the flow rate of at least one of the first fluid (hydrogel precursor), the second fluid (gelator), and the third fluid to eliminate the deviation.

[0103] As described above, the flow rates of the first, second, and third fluids have a relationship with the shell diameter R1, the core diameter R2, and / or the ratio (S3 / S1) of the core cross-sectional area S3 to the shell cross-sectional area S1, as shown in Table 1. Based on this relationship, the control device 900 can change the flow rate of at least one of the first, second, and third fluids so that the size of the hydrogel actually formed approaches the set value of the hydrogel size input by the user.

[0104] Instead of or in addition to the above analysis, the analysis unit 920 may be configured to estimate the density of contaminants, such as cells, in 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, instead of or in addition to the above analysis, the analysis unit 920 may be configured to calculate the transparency of the image captured by the imaging unit 800 and estimate the density of contaminants, such as cells, in the hydrogel based on the transparency. Specifically, when the third fluid contains cells, the analysis unit 920 calculates the transparency of a core in the hydrogel in the image captured by the imaging unit 800. The analysis unit 920 estimates the cell density in the core of the hydrogel based on the transparency of the core.

[0105] When the third fluid contains cells, the transparency of the third fluid or core is closely related to the density of cells in the third fluid. That is, the higher the cell density in the third fluid, the lower the transparency of the third fluid or core. Therefore, the analysis unit 920 can estimate the cell density in the core of the formed hydrogel based on the transparency of the core in the formed hydrogel. The relationship between the transparency of the core and the cell density may be determined in advance through experiments. This allows the hydrogel manufacturing apparatus 100 to quantitatively measure and store the density of cells mixed into the hydrogel, for example, in cell culture experiments.

[0106] The analysis unit 920 may be configured to detect an abnormality 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 imaging unit 800. The control device 900 may 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 the abnormality is detected.

[0107] Furthermore, the analysis unit 920 may be configured to detect an abnormality in the third flow path 232 by analyzing the image (image information) captured by the imaging unit 800. In this case, the control device 900 may be configured to stop the delivery of at least one, and preferably all, of the first fluid (hydrogel precursor), the second fluid (gelling agent), and the third fluid when an abnormality is detected.

[0108] Here, when detecting an abnormality in the first flow path 212, the second flow path 222 and / or the third flow path 232, the imaging 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.

[0109] The detected abnormality of the hydrogel may be an abnormality in the size of the hydrogel, a significant variation in the shape of the hydrogel, and / or non-formation of the hydrogel, etc. The detected abnormality of the first flow path 212, the second flow path 222, and the third flow path 232 may be a blockage of the flow path, a turbulence in the flow, a deviation in the coaxial flow of the first fluid, the second fluid, and the third fluid, etc.

[0110] Furthermore, the control device 900 may 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 it detects a pressure abnormality in at least one of the first flow path 212, the second flow path 222, and the third flow path 232. The pressure abnormality can be detected, for example, by the pressure sensor 616 described above.

[0111] If the analysis unit 920 detects an abnormality in the hydrogel to 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.

[0112] The display device 980 may be configured to be able to display a schematic diagram of at least one, preferably a plurality of, and more preferably all of 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 state of each flow path along with the name of each flow path.

[0113] (Method for Producing Hydrogel) Next, a method for producing a hydrogel will be described with reference to FIGS. 7 to 13. FIG. 7 is a schematic diagram illustrating the state of each introduction channel at the initial stage of a leak test. FIG. 8 is a schematic diagram illustrating the state of each introduction channel at a stage subsequent to FIG. 7. FIG. 9 is a schematic diagram illustrating the state of each introduction channel at a stage subsequent to FIG. 8. FIG. 10 is a schematic diagram illustrating the state of each introduction channel at a preliminary liquid transfer (pre-liquid transfer) stage. FIG. 11 is a schematic diagram illustrating the state of each introduction channel at a preparation stage for a pulsation suppression means and / or a debubbling means. FIG. 12 is a schematic diagram illustrating the state of each introduction channel at a stage subsequent to FIG. 11. FIG. 13 is a schematic diagram illustrating the state of each introduction channel at a stage during the formation of a hydrogel.

[0114] (1) Preparation In the method for producing a hydrogel, first, the flow path forming member 200 is set in the housing 120. Specifically, the first flow path 212 of the flow path forming member 200 is connected to the first inlet path 132, the second flow path 222 of the flow path forming member 200 is connected to the second inlet path 134, and the third flow path 232 of the flow path forming member 200 is connected to the third inlet path 136.

[0115] Also, a first fluid is placed in first reservoir 102, a second fluid is placed in second reservoir 104, and a third fluid is placed in third reservoir 106. If necessary, a cleaning solution is placed in cleaning container 108.

[0116] Here, the hydrogel flow path 300 and the container 400 do not yet need to be connected to the flow path forming member 200. Instead, it is desirable to seal the outlet 240 side of the flow path forming member 200.

[0117] (2) Leak Inspection Next, a leak inspection is performed on the first inlet passage 132, the second inlet passage 134, and the third inlet passage 136. Specifically, it is checked whether the first inlet passage 132, the second inlet passage 134, and the third inlet passage 136 are airtight and / or liquidtight. Alternatively, or in addition to this, it is checked whether the flow path forming member 200 is connected to the first inlet passage 132, the second inlet passage 134, and the third inlet passage 136 in an airtight and / or liquidtight manner.

[0118] In the initial stage of the leak test, all of the valves described above, i.e., the first introduction valve 162, the second introduction valve 164, the third introduction valve 166, the fourth introduction valve 172, the fifth introduction valve 174, the sixth introduction valve 176, the cleaning valve 168, and the air valves 182, 184, and 186, may be closed (see FIG. 7). Here, in FIGS. 7 to 13, the blackened valves indicate that the valves are closed. On the other hand, the unblackened valves indicate that the valves are open.

[0119] Next, the air valves 182, 184, 186 are opened, and the first pump 112, the second pump 114, and the third pump 116 are operated to introduce gas into the first inlet passage 132, the second inlet passage 134, and the third inlet passage 136, and it is checked whether there is a leak (see FIG. 8). Here, in FIGS. 7 to 13, the dotted shapes of the flow paths and inlet passages indicate that gas is being introduced.

[0120] More specifically, it is checked whether there are any leaks in the first inlet passage 132, the second inlet passage 134, and the third inlet passage 136 upstream of the fourth inlet valve 172, the fifth inlet valve 174, and the sixth inlet valve 176.

[0121] Next, the fourth inlet valve 172 is opened, and it is checked whether there is a leak in the first inlet passage 132 downstream of the fourth inlet valve 172 (see FIG. 9 ). Here, the first inlet passage 132 is in communication with the second inlet passage 134 and the third inlet passage 136 via the flow path forming member 200, so the fifth inlet valve 174 and the sixth inlet valve 176 may be closed. This makes it possible to check, in particular, whether the first flow path 212 and the first inlet passage 132 are in airtight and / or liquidtight communication.

[0122] Furthermore, the fourth inlet valve 172 is closed and the fifth inlet valve 174 is opened to check whether there is a leak in the second inlet passage 134 downstream of the fifth inlet valve 174. At this time, the fourth inlet valve 172 and the sixth inlet valve 176 may be closed. This makes it possible to check, in particular, whether the second flow path 222 and the second inlet passage 134 are in airtight and / or liquidtight communication.

[0123] Furthermore, the fifth inlet valve 174 is closed and the sixth inlet valve 176 is opened to check whether there is a leak in the third inlet passage 136 downstream of the sixth inlet valve 176. At this time, the fourth inlet valve 172 and the fifth inlet valve 174 may be closed. This makes it possible to check, in particular, whether the third flow path 232 and the third inlet passage 136 are in airtight and / or liquidtight communication.

[0124] Here, the check for leaks in the first inlet passage 132, the second inlet passage 134, and the third inlet passage 136 may be performed in any order. Furthermore, the occurrence of a leak in each inlet passage can be detected, for example, from the pressure value or pressure fluctuation value measured by the pressure sensor 616 connected to each inlet passage.

[0125] Once the leak test is complete, all of the valves mentioned above, namely, the first introduction valve 162, the second introduction valve 164, the third introduction valve 166, the fourth introduction valve 172, the fifth introduction valve 174, the sixth introduction valve 176, the cleaning valve 168, and the air valves 182, 184, and 186, may be closed.

[0126] (3) Preliminary Liquid Delivery (Preliminary Liquid Delivery) Next, the outlet 240 of the flow path forming member 200 and the storage container 400 are airtightly and / or liquid-tightly communicated by the hydrogel flow path 300. Then, liquid is preliminarily delivered to the storage container 400 through the hydrogel flow path 300 (preliminary liquid delivery).

[0127] In the pre-liquid transfer, the cleaning liquid is preferably transferred to the storage container 400 through the outlet 240 of the flow path forming member 200 and the hydrogel flow path 300. Specifically, the cleaning valve 168 and the fifth introduction valve 174 are opened, and the second pump 114 is driven to transfer the cleaning liquid (see FIG. 10 ). In FIG. 10 , the flow paths with a solid pattern indicate the portions into which the cleaning liquid is introduced.

[0128] The cleaning liquid passes through the cleaning flow path 138, the second inlet path 134, the second flow path 222, and the first junction 216, and reaches the outlet 240. Furthermore, the cleaning liquid passes through the hydrogel flow path 300 and reaches the storage container 400.

[0129] The purpose of the pre-liquid transfer is to wet the inner surface of the tube that constitutes the hydrogel flow channel 300. This makes it possible to prevent the hydrogel formed in a later stage from sticking to the inner surface of the tube that constitutes the hydrogel flow channel 300.

[0130] In the above embodiment, the cleaning liquid is pumped through the hydrogel channel in the pre-fluiding step. Alternatively, the fluid pumped through the hydrogel channel in the pre-fluiding step may be a liquid other than the cleaning liquid. For example, the fluid pumped through the hydrogel channel may be any of the first fluid, the second fluid, and the third fluid. For the purposes of suppressing cell loss and reducing costs, the fluid pumped through the hydrogel channel is preferably the cleaning liquid or the second fluid.

[0131] Once the pre-liquid transfer is complete, all of the valves mentioned above, namely, the first introduction valve 162, the second introduction valve 164, the third introduction valve 166, the fourth introduction valve 172, the fifth introduction valve 174, the sixth introduction valve 176, the cleaning valve 168, and the air valves 182, 184, and 186, can be closed.

[0132] (4) Preparation of Pulsation Suppression Means and / or Defoaming Means Preparation of the pulsation suppression means and / or defoaming means is performed as needed and need not be performed if not required. In this preparation, the first introduction valve 162, the second introduction valve 164, and the third introduction valve 166 are opened, and the first pump 112, the second pump 114, and the third pump 116 are operated to send the first fluid, the second fluid, and the third fluid ( FIG. 11 ). The first fluid, the second fluid, and the third fluid are sent to the storage section 612 that constitutes the pulsation suppression means 610, 620, and 630 and / or the defoaming means 710, 720, and 730, respectively. In FIG. 11 , the solid-colored flow paths indicate the portions into which the first fluid, the second fluid, or the third fluid is introduced.

[0133] As the first, second, and third fluids are sent to the container 612, the pressure inside the container 612 increases. Next, a valve provided at the pressure sensor 616 is opened as shown in Figure 12, and the pressure inside the container 612 is adjusted to a desired value range (see Figure 12). After this step is completed, the valve provided at the pressure sensor 616 can be closed.

[0134] (5) Stage During Hydrogel Formation Next, a hydrogel is formed. The hydrogel production method using the above-described hydrogel production apparatus includes flowing a third fluid toward the third flow path 232, flowing a first fluid (hydrogel precursor) into the first flow path 212, flowing a second fluid (gelling agent) into the second flow path 222, and causing the hydrogel precursor and the gelling agent to merge at the first junction 216 to form a hydrogel.

[0135] Specifically, the first introduction valve 162, the second introduction valve 164, the third introduction valve 166, the fourth introduction valve 172, the fifth introduction valve 174, and the sixth introduction valve 176 are opened, and the first pump 112, the second pump 114, and the third pump 116 are operated to deliver the first, second, and third fluids (see FIG. 13 ). Preferably, the second operating unit 107 may be operated before delivering the third fluid to move (shake, vibrate, or the like) the third fluid in the third reservoir 106. If the third fluid contains suspended particles such as cells, the action of the second operating unit 107 can uniformly disperse the suspended particles in the third fluid.

[0136] Preferably, the first, second, and third fluids are continuously delivered at a constant flow rate. This forms a laminar flow at the first junction 216, in which the third fluid, the first fluid, and the second fluid are arranged in this order radially outward from the center. In this state, the first fluid (hydrogel precursor) is gelled by the second fluid (gelling agent), forming a tubular hydrogel containing the first fluid therein (see FIGS. 4 and 5 ). The length of the tubular hydrogel can be adjusted by adjusting the delivery times of the first, second, and third fluids.

[0137] The hydrogel formed in the flow path forming member 200 is introduced into the storage container 400 through the hydrogel flow path 300 .

[0138] [Second Embodiment] Fig. 14 is a schematic diagram for explaining the structure of a flow path of a hydrogel-producing apparatus according to a second embodiment. Fig. 15 is a block diagram of the hydrogel-producing apparatus according to the second embodiment. It should be noted that in the second embodiment, explanations of components similar to those in the first embodiment may be omitted. Furthermore, components identical to or corresponding to those described in the first embodiment are denoted by the same reference numerals.

[0139] In the second embodiment, the hydrogel-producing apparatus 100 may include a first reservoir 102, a second reservoir 104, and a flow path component 200. The first reservoir 102 stores a first fluid. The first fluid is a hydrogel precursor. Details of the hydrogel precursor are as described in the first embodiment.

[0140] The second reservoir 104 stores a second fluid (gelling agent) that gels the first fluid (hydrogel precursor) upon contact with the first fluid. Details of the gelling agent are as described in the first embodiment.

[0141] The flow path forming member 200 is a member including flow paths for a first fluid and a second fluid. The flow path forming member 200 may have a first inlet 210, a second inlet 220, and an outlet 240. The first inlet 210 is an inlet for the first fluid. The second inlet 220 is an inlet for the second fluid. The flow path forming member 200 may have a first flow path 212 and a second flow path 222.

[0142] It should be noted that the second embodiment does not have the third reservoir 106 or the third flow path described in the first embodiment.

[0143] The first flow path 212 is a flow path for flowing the hydrogel precursor, and may be defined by a flow path from the first inlet 210 to the outlet 240 via a first junction 216 described below. The second flow path 222 may be defined by a flow path from the second inlet 220 to the first junction 216.

[0144] The second flow path 222 is configured to merge the second fluid (gelling agent) around the first fluid in the first flow path 212 at the first junction 216. This causes the second fluid to flow around the first fluid in the same direction as the flow of the first fluid. That is, the second fluid surrounds the first fluid (hydrogel precursor) in a cross section perpendicular to the flow of the first fluid.

[0145] The hydrogel manufacturing apparatus 100 may include a first pump 112 that delivers a first fluid and a second pump 114 that delivers a second fluid.

[0146] A hydrogel manufacturing method using the hydrogel manufacturing apparatus according to 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 causing the hydrogel precursor and gelling agent to merge at a first junction 216 to form a hydrogel.

[0147] Preferably, the first fluid and the second fluid are continuously delivered at a constant flow rate, thereby forming a laminar flow in which the first fluid and the second fluid are arranged in this order from the center to the outside in the radial direction at the first junction 216. In this state, the first fluid (hydrogel precursor) is gelled by the second fluid (gelling agent), thereby forming a string-like hydrogel (solid hydrogel) (see FIGS. 16 and 17 ).

[0148] The hydrogel formed in the flow path forming member 200 is introduced into the storage container 400 through the hydrogel flow path 300 .

[0149] Fig. 16 is a perspective view showing an example of the structure of the hydrogel formed in the second embodiment. Fig. 17 is a cross-sectional view of the hydrogel shown in Fig. 16. As shown in Fig. 16, a solid hydrogel 10 is formed in the shape of a long, stretched string.

[0150] The first fluid may contain cells. When the first fluid contains cells, the cells are embedded in the formed string-like hydrogel. In this case, the storage container 400 may be, for example, a culture container for culturing cells. The type of cells is as described in the first embodiment.

[0151] The hydrogel-manufacturing apparatus 100 may include a first pulsation suppression means 610 and / or a second pulsation suppression means 620. The hydrogel-manufacturing apparatus 100 may also include a first defoaming means 710 and / or a second defoaming means 720. The configurations of the first pulsation suppression means 610, the second pulsation suppression means 620, the first defoaming means 710 and / or the second defoaming means 720 are as described in the first embodiment.

[0152] In an 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. In other words, a 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 be configured to receive one of the flow rate of the first flow path and the flow rate of the second flow path. The command unit 930 sends commands to operate the first pump 112 and the second pump 114 based on the input values ​​received by the input unit 910.

[0153] Here, the flow rates of the first fluid and the second fluid affect the size of the formed string-like hydrogel. Specifically, the flow rate V1 of the first fluid and the flow rate V2 of the second fluid affect the diameter R1 of the formed tubular hydrogel. More specifically, the larger the ratio of the flow rate of the first fluid to the flow rate of the second fluid (V1 / V2), the larger the diameter R1 of the hydrogel.

[0154] Therefore, the user can appropriately adjust the diameter R1 of the string-like hydrogel that is formed by appropriately setting the flow velocity V1 of the first fluid and the flow velocity V2 of the second fluid.

[0155] The analysis unit 920 may calculate a value related to the size of the formed hydrogel. Specifically, the analysis unit 920 preferably calculates the diameter R1 of the formed hydrogel.

[0156] The storage unit 940 may store the results of the analysis performed by the analysis unit 920 in association with the value of the flow rate set by the input unit 910. The value relating to the size of the hydrogel calculated by the analysis unit 920, for example, the diameter R1, is preferably stored in the storage unit 940 in association with information relating to the flow rate V1 of the first fluid and the flow rate V2 of the second fluid during the production of the hydrogel.

[0157] 18 is a diagram showing an example of data stored in the storage unit in Embodiment 2. As shown in Fig. 18 , the diameter R1 of the hydrogel calculated by the analysis unit 920 may be stored in the storage unit 940 in association with the flow velocity V1 of the first fluid and the flow velocity V2 of the second fluid during the production of the hydrogel.

[0158] Similar to the first embodiment, the input unit 910 may be configured to receive information regarding the size of the hydrogel to be formed. For example, the input unit 910 may be configured to receive the diameter R1 of the hydrogel to be formed.

[0159] When the control device 900 receives information about the size of the hydrogel to be formed, such as the diameter R1 of the hydrogel, input by the user, 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 about 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, from information about the size of hydrogels previously manufactured. Specifically, the control device 900 can determine at least one of the flow rate V1 of the first fluid and the flow rate V2 of the second fluid based on past data stored in the storage unit 940 (see FIG. 10 ), i.e., the relationship between the flow rate V1 of the first fluid, the flow rate V2 of the second fluid, and the size (diameter R1) of the hydrogel. Here, the control device 900 may determine only one of the flow rate V1 of the first fluid and the flow rate V2 of the second fluid based on information regarding the size of the hydrogel to be formed input by the user, for example, the diameter R1 of the hydrogel, and the user may determine the other of the flow rate V1 of the first fluid and the flow rate V2 of the second fluid.

[0160] The control device 900 may be configured to control (feedback control) the flow rate of at least one of the first fluid (hydrogel precursor) and the second fluid (gelator) based on the results of analysis by the analysis unit 920. Specifically, the analysis unit 920 calculates the diameter R1 of the actually formed hydrogel based on the image of the formed hydrogel, as described above. Furthermore, the analysis unit 920 calculates the deviation of the diameter R1 of the actually formed hydrogel from the set value of the hydrogel diameter received by the input unit 910. The command unit 930 may control, i.e., change, the flow rate of at least one of the first fluid (hydrogel precursor) and the second fluid (gelator) to eliminate the deviation.

[0161] As described above, the larger the ratio (V1 / V2) between the flow rates of the first and second fluids, 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 and second fluids so that the size of the hydrogel actually formed approaches the value of the hydrogel size input by the user.

[0162] The method for producing a hydrogel in the second embodiment can be carried out in substantially the same manner as the method described in the first embodiment. However, since the third flow path and its associated components are not provided in the second embodiment, the steps associated with the third flow path and its associated components among the steps described in the production method described in the first embodiment may be omitted.

[0163] As described above, the contents of the present invention have been disclosed through embodiments and examples, but the descriptions and drawings that form part of this disclosure should not be understood to limit the present invention. Various alternative embodiments, examples, and operating techniques will become apparent to those skilled in the art from this disclosure. Therefore, the technical scope of the present invention is defined only by the inventive features of the claims that can be reasonably understood from the above description.

[0164] 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 comprising: a first flow path for flowing a hydrogel precursor; a second flow path for flowing a gelling agent that gels the hydrogel precursor; a first junction of the first flow path and the second flow path; a storage container for storing a hydrogel formed by contact of the hydrogel precursor with the gelling agent; and a hydrogel flow path providing closed communication at least between the storage container and the first junction.

2. The hydrogel manufacturing apparatus according to claim 1, wherein the storage container is a flexible container having an expandable and contractable internal space.

3. The hydrogel manufacturing apparatus according to claim 1 or 2, wherein the hydrogel flow path is constituted by a flexible tube.

4. A hydrogel manufacturing apparatus according to any one of claims 1 to 3, comprising a first operating unit for moving the liquid in the storage container.

5. A hydrogel manufacturing apparatus according to any one of claims 1 to 4, wherein the container is a culture container for culturing cells.

6. A hydrogel manufacturing apparatus as described in any one of claims 1 to 5, having a pulsation suppression means for suppressing pulsation of the hydrogel precursor and / or gelling agent upstream of the first confluence.

7. A hydrogel manufacturing apparatus as described in any one of claims 1 to 6, having a defoaming means upstream of the first junction for removing bubbles in a solution containing a hydrogel precursor and / or a gelling agent.

8. The hydrogel manufacturing apparatus according to claim 7, wherein the debubbling means is located between the pump and the first junction and has a storage section capable of holding gas.

9. A hydrogel manufacturing apparatus according to any one of claims 1 to 8, comprising a pump for flowing the hydrogel precursor and / or the gelling agent, the pump having a performance such that, at a specific average flow rate value within a range of 0.1 mL / min to 1000 mL / min, the fluctuation amount of the flow rate is within 20% of the specific average flow rate value, except at the time of starting and stopping.

10. A hydrogel manufacturing apparatus described in any one of claims 1 to 9, having an imaging unit that captures the morphology of the hydrogel downstream of the first confluence or at the first confluence.

11. The hydrogel manufacturing apparatus described in claim 10, further comprising: an analysis unit that analyzes the morphology of the hydrogel imaged by the imaging unit; and a control device that controls the flow rate of at least one of the hydrogel precursor and the gelling agent based on the results of the analysis by the analysis unit.

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

13. A hydrogel manufacturing apparatus as described in claim 11 or 12, comprising: an input unit for setting the flow rate of at least one of the hydrogel precursor and the gelling agent; and a memory unit for storing the results of analysis by the analysis unit together with the value of the flow rate set by the input unit.

14. A hydrogel manufacturing apparatus as described in any one of claims 1 to 13, comprising a third flow path for flowing a fluid, the third flow path being configured to merge with the first flow path at a second junction upstream of the first junction.

15. The hydrogel manufacturing apparatus according to claim 14, further comprising: a third reservoir for storing the fluid; and a second operating unit for moving the fluid in the third reservoir.

16. A hydrogel manufacturing apparatus as described in claim 15, comprising: an imaging unit that acquires the morphology of the hydrogel downstream of the first junction or at the first junction; an analysis unit that analyzes the morphology of the hydrogel imaged by the imaging unit; and 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 of the analysis by the analysis unit.

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

18. A hydrogel manufacturing apparatus as described in any one of claims 15 to 17, comprising: an input unit for setting a flow rate of at least one of the hydrogel precursor, the gelling agent, and the fluid; and a memory unit for storing the results of the analysis by the analysis unit together with the value of the flow rate set by the input unit.

19. A hydrogel manufacturing apparatus as described in any one of claims 11 to 13 and 15 to 18, wherein the analysis unit detects an abnormality in at least one of the hydrogel, the first flow path and the second flow path, and the control device is configured to stop the delivery of the hydrogel precursor and the gelling agent when the abnormality is detected.

20. A hydrogel manufacturing apparatus as described in any one of claims 1 to 19, comprising a flow path forming member in which the first flow path and the second flow path are formed, the flow path forming member having an outlet for discharging a hydrogel formed from a hydrogel precursor and a gelling agent, and the distance from the first junction to the outlet is in the range of 3 mm to 150 mm.

21. A hydrogel manufacturing apparatus as described in any one of claims 1 to 20, wherein the hydrogel flow path is constituted by a tube made of a rigid body.

22. A method for producing a hydrogel using a hydrogel production apparatus described in any one of claims 1 to 21, comprising: flowing a hydrogel precursor into the first flow path; flowing a gelling agent into the second flow path; causing the hydrogel precursor and the gelling agent to merge at the first junction to form a hydrogel; and introducing the formed hydrogel into the storage container through the hydrogel flow path.

23. A hydrogel manufacturing method as described in claim 22, wherein the storage container is a flexible container having an expandable and contractible internal space, and the internal space of the storage container is made expandable before the hydrogel precursor and the gelling agent are delivered.

24. The method for producing a hydrogel according to claim 22 or 23, further comprising the step of performing pre-liquidation by passing a liquid through a hydrogel flow path prior to the formation of the hydrogel.

25. A method for producing a hydrogel according to any one of claims 22 to 24, comprising inspecting a flow path included in the hydrogel production apparatus for leaks prior to forming the hydrogel.

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