Method for manufacturing microcapsules and apparatus for manufacturing microcapsules

Abstract

To provide a method for manufacturing microcapsules with reduced particle size variation, and to provide a microcapsule manufacturing apparatus capable of facilitating the production of microcapsules controlled within a desired particle size range.SOLUTION: The method for manufacturing microcapsules comprises a step of: depositing droplets of a first solution ejected from an inkjet-type ejection head onto a second solution stored in the direction of droplet ejection, thereby forming microcapsules covered with a hydrogel membrane, wherein a first solution contains a first substrate, and a second solution contains a second substrate that reacts with the first substrate to form a hydrogel, and wherein during the microcapsule formation step, droplets are dispensed while altering the droplet dispensing position at the surface of the second solution.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to a method and an apparatus for producing microcapsules. [Background technology]

[0002] Encapsulation technology has been used to produce microparticles (microcapsules) containing desired substances. For example, microcapsules containing cells have been investigated for application in medical fields such as cell transplantation therapy by using biocompatible hydrogels as the encapsulating material for the cells.

[0003] A known method for producing microcapsules involves ejecting a first polymer electrolyte solution containing a first polymer electrolyte from the tip of a needle and contacting the resulting microdroplets with a second polymer electrolyte solution containing a second polymer electrolyte to form a polymer film on the droplet surface, thereby obtaining microcapsules (see, for example, Patent Document 1).In the invention described in Patent Document 1, by adding a predetermined substance such as cells to the first polymer electrolyte solution, microcapsules encapsulating the added predetermined substance are obtained. Summary of the Invention [Problem to be solved by the invention]

[0004] In the invention described in Patent Document 1, when the first polymer electrolyte solution is ejected from the tip of the needle, a voltage is applied to the needle to strongly charge the droplets that are formed. This causes the charged droplets to fly, suppresses the droplets from coalescing during flight, and produces microcapsules of uniform size.

[0005] However, in this method, the falling position of the formed droplets on the liquid surface of the second polymer electrolyte solution is not controlled, and therefore, if the droplets fall so as to overlap with microcapsules formed with the second polymer electrolyte solution, they may overlap with the already formed microcapsules to form further microcapsules, which may result in variations in the size (particle diameter) of the resulting microcapsules.

[0006] The present invention has been made in view of the above circumstances, and aims to provide a method for producing microcapsules with reduced variation in particle size, and a microcapsule production apparatus that can easily produce microcapsules with particle size controlled to a desired range. [Means for solving the problem]

[0007] In order to solve the above problems, one aspect of the present invention provides a method for manufacturing microcapsules, which includes a step of dropping droplets of a first solution ejected from an inkjet ejection head onto a second solution stored in the ejection direction of the droplets, to form microcapsules covered with a hydrogel membrane, wherein the first solution contains a first substrate and the second solution contains a second substrate that reacts with the first substrate to form the hydrogel, and in the step of forming the microcapsules, the droplets are dropped while changing their dropping position on the liquid surface of the second solution. [Effects of the Invention]

[0008] According to the present invention, it is possible to provide a method for producing microcapsules with reduced variation in particle size, and also to provide a microcapsule production device that can easily produce microcapsules with particle size controlled within a desired range. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 is a schematic diagram of a microcapsule manufacturing apparatus 1 of this embodiment. [Figure 2]FIG. 2 is a partially enlarged view of the microcapsule manufacturing apparatus 1. [Figure 3] FIG. 3 is a partially enlarged view of the microcapsule manufacturing apparatus 1. [Figure 4] FIG. 4 is a partially enlarged view of the microcapsule manufacturing apparatus 1. DETAILED DESCRIPTION OF THE INVENTION

[0010] The microcapsule manufacturing method and microcapsule manufacturing apparatus according to this embodiment will be described below with reference to Figures 1 to 4. In all of the following figures, the dimensions and proportions of the components have been appropriately changed to make the drawings easier to understand.

[0011] In the following explanation, an xyz Cartesian coordinate system is set, and the positional relationship of each component is explained with reference to this xyz Cartesian coordinate system. Here, a specific direction in a horizontal plane is defined as the x direction, a direction perpendicular to the x direction in the horizontal plane is defined as the y direction, and a direction perpendicular to both the x and y directions (i.e., the vertical direction) is defined as the z direction.

[0012] In addition, the vertically upward direction is the +z direction, and the vertically downward direction is the -z direction. In the following explanation, the "upper" in "upper" and "upper surface" and the "lower" in "lower" and "lower surface" have the same meaning.

[0013] Furthermore, in the following description, "planar view" refers to viewing an object from above (+z direction), and "planar shape" refers to the shape of an object viewed from above.

[0014] "Microcapsule MC" In the microcapsule manufacturing apparatus and method of this embodiment, a droplet DR of a first solution L1 containing a first substrate is ejected and brought into contact with a second solution L2 containing a second substrate that reacts with the first substrate to form a hydrogel, thereby producing a microcapsule MC in which a core C is covered with a hydrogel membrane HM (see FIG. 1).

[0015] The first solution L1 also contains a substance dissolved or dispersed therein that is to be encapsulated in the resulting microcapsules MC. Such a substance contained in the first solution L1 and intended to be encapsulated in the microcapsules MC may be referred to hereinafter as the "encapsulated substance." As a result, the resulting microcapsules MC become particles that contain (encapsulate) the encapsulated substance.

[0016] (1st substrate, 2nd substrate) The first substrate and the second substrate are not particularly limited as long as they form a crosslinked structure and gel when mixed together, and can be appropriately selected depending on the purpose.

[0017] Specific examples of the first substrate include biopolymers such as collagen, elastin, gelatin, and fibroin; coagulation factors such as fibrinogen; adhesion factors such as fibronectin, laminin, and recombinant peptides; metal salts of polysaccharide compounds such as alginic acid and gellan gum; and synthetic polymers such as polylactic acid and polyethylene glycol. These may be used alone or in combination of two or more.

[0018] Specific examples of the second substrate include polysaccharides, polyvalent metal salts, fibrinogen, thrombin, fibronectin, laminin, recombinant peptides, chitosan, chitin, tetrafunctional polyethylene glycol (Tetra-PEG), etc. These may be used alone or in combination of two or more.

[0019] It is advisable to carry out a preliminary experiment in advance to determine the combination of the first substrate and the second substrate that will give a hydrogel with the desired physical properties.

[0020] The resulting hydrogel is preferably a material that functions as a scaffold for cell culture. For example, when sodium alginate is used as the first substrate and a calcium salt such as calcium chloride is used as the second substrate, the resulting hydrogel (calcium alginate) is a material that can be used as a cell scaffold for research purposes and is preferred.

[0021] The solvent (dispersion medium) of the first solution L1 is not particularly limited as long as it is an aqueous solution that can dissolve the first substrate and dissolve or disperse the encapsulated substance. When cells are used as the encapsulated substance, the dispersion medium can be a known buffer solution such as phosphate buffered saline or Hank's balanced salt solution, or a culture medium suitable for the cells used.

[0022] The solvent (dispersion medium) of the second solution L2 is not particularly limited as long as it is an aqueous solution that can dissolve the second substrate and dissolve or disperse the encapsulated substance. The solvent (dispersion medium) of the second solution L2 can be the same as the solvent (dispersion medium) of the first solution L1 described above.

[0023] (cell) A representative example of the encapsulated substance contained in the first solution L1 is cells. By using cells as the encapsulated substance, the resulting microcapsules MC become hydrogel particles encapsulating cells.

[0024] There are no particular restrictions on the type of cells, and they can be selected appropriately depending on the purpose. All cells can be used, regardless of taxonomic classification, for example, karyotic cells, prokaryotic cells, multicellular organism cells, or unicellular organism cells.

[0025] Examples of eukaryotic cells include animal cells, insect cells, plant cells, and fungi. These may be used alone or in combination of two or more. Among these, animal cells are preferred, and when the cells form cell aggregates, adhesive cells that adhere to each other and have such cell adhesiveness that they cannot be isolated without physicochemical treatment are more preferred.

[0026] There are no particular limitations on the adhesive cells, and they can be appropriately selected depending on the purpose. Examples include differentiated cells and undifferentiated cells.

[0027] Examples of differentiated cells include hepatocytes, which are parenchymal cells of the liver; stellate cells; Kupffer cells; vascular endothelial cells; endothelial cells such as meatal endothelial cells and corneal endothelial cells; fibroblasts; osteoblasts; osteoclasts; periodontal ligament-derived cells; epidermal cells such as epidermal keratinocytes; tracheal epithelial cells; digestive tract epithelial cells; cervical epithelial cells; epithelial cells such as corneal epithelial cells; mammary gland cells; pericytes; muscle cells such as smooth muscle cells and cardiac muscle cells; kidney cells; pancreatic islet cells of Langerhans; nerve cells such as peripheral nerve cells and optic nerve cells; chondrocytes; bone cells, etc. The adhesive cells may be primary cells directly collected from tissues or organs, or may be cells that have been passaged for several generations.

[0028] The undifferentiated cells are not particularly limited and can be appropriately selected depending on the purpose. Examples include undifferentiated cells such as embryonic stem cells and pluripotent stem cells such as mesenchymal stem cells that have the ability to differentiate into different types; unipotent stem cells such as vascular endothelial progenitor cells that have the ability to differentiate into a single type; and iPS cells.

[0029] The above-mentioned cells may form a cell cluster (spheroid), that is, a cell cluster can also be used as an encapsulation substance.

[0030] The microcapsules MC obtained in this manner have a core-shell structure in which the first solution L1 is encapsulated as the core C and the membrane HM encases the core C. Since the core C contains the first substrate, the first substrate of the core C may also react with the second substrate to solidify (gel).

[0031] The microcapsule manufacturing apparatus of this embodiment can suitably perform the formation of the droplets DR of the first solution L1 and the reaction of the droplets DR with the second solution L2.

[0032] [Microcapsule manufacturing equipment] Fig. 1 is a schematic diagram of a microcapsule manufacturing apparatus 1 of this embodiment. Figs. 2 to 4 are partial enlarged views of the microcapsule manufacturing apparatus 1. As shown in Figs. 1 to 4, the microcapsule manufacturing apparatus 1 has a discharge unit 10, a position changing member 21, a storage unit 30, a placement unit 40, and a control unit 50. In the following description, the microcapsule manufacturing apparatus may be simply abbreviated as "manufacturing apparatus."

[0033] 《Discharge part》 As shown in FIG. 1, the ejection unit 10 includes an ejection head 110 and a transport unit 120.

[0034] <Discharge head> The ejection head 110 employs a so-called inkjet method, and ejects the first solution L1 held in the ejection head 110 to form droplets DR.

[0035] The "inkjet method" is a method of ejecting liquid, which is the material for droplets, in small amounts with high precision from the nozzles of an ejection head. In an ejection head that uses the inkjet method, stress such as pressure or inertial force is applied instantaneously to the liquid stored in the ejection head. As a result, the liquid in the ejection head near the nozzle separates into tiny liquid particles in response to the applied stress, forming droplets.

[0036] For example, when producing microcapsules encapsulating cells using the method described in Patent Document 1, the cells are exposed to an electrically charged environment while droplets are sprayed from a needle and inside the flying droplets. Therefore, the method described in Patent Document 1 applies electrical stimulation to the cells during production of the microcapsules, raising concerns about adverse effects on the cells. Furthermore, even when encapsulating desired substances other than cells in the microcapsules, it is necessary to consider the effects of exposure to an electrically charged environment, which makes the method less versatile.

[0037] In contrast, with the inkjet discharge head 110, the first solution L1 is not exposed to a charged environment when forming the droplets DR. Therefore, when the first solution L1 is a dispersion of cells, using the inkjet discharge head 110 eliminates the need to consider adverse electrical effects on the cells.

[0038] The discharge section 10 may have only one or more discharge heads 110. The discharge section 10 shown in Fig. 1 has three discharge heads 110a, 110b, and 110c. The three discharge heads 110a, 110b, and 110c are collectively referred to as a discharge unit 110L.

[0039] The ejection heads 110a, 110b, and 110c may have the same configuration or may have different configurations.

[0040] The three ejection heads 110a, 110b, and 110c are arranged in a direction (x direction in the drawing) that intersects with the ejection direction of the liquid ejected from the ejection head 110 (-z direction in the drawing).

[0041] As shown in FIG. 2, the ejection head 110 includes a liquid holding portion 111, a vibration portion 115, and a fixing member 117.

[0042] The space surrounded by the liquid holding section 111 and the vibration section 115 is a liquid chamber 110S of the ejection head 110. The liquid chamber 110S holds a liquid (first solution L1) that is the source of droplets DR.

[0043] The amount of the first solution L1 held in the liquid chamber 110S is not particularly limited. For example, the amount of the first solution L1 held in the liquid chamber 110S may be approximately 1 μl to 1 ml. When an expensive liquid such as a cell suspension is discharged from the manufacturing apparatus 1, the amount of the first solution L1 held in the liquid chamber 110S may be approximately 1 μl to 200 μl.

[0044] The ejection heads 110a, 110b, and 110c may each hold the same first solution L1, or may each hold a different first solution L1.

[0045] (liquid holding part) The liquid holder 111 is a tubular member with both ends in the z direction open. The liquid holder 111 may be, for example, a cylindrical member. Examples of materials for the liquid holder 111 include metals such as stainless steel, nickel, and aluminum, plastics (resin materials) such as ABS, polycarbonate, and fluororesin, ceramics such as silicon dioxide, alumina, and zirconia, and silicon.

[0046] One end of the liquid holding unit 111, that is, the lower end, is covered and blocked by the vibration unit 115. The other end of the liquid holding unit 111, that is, the upper end, is open to the atmosphere. When the upper part of the liquid holding unit 111 is open to the atmosphere, the first solution L1 held in the liquid holding unit 111 is less likely to be pressurized when droplets are ejected. Therefore, when cells are contained in the first solution L1, damage to the cells can be suppressed.

[0047] (vibration part) The vibration unit 115 includes a nozzle plate (film-like member) 112 and a vibration member 113 . The vibration unit 115 shown in FIG. 2 has the vibration member 113 positioned above and the nozzle plate 112 positioned below, but is not limited to this, and the nozzle plate 112 may be positioned above and the vibration member 113 below.

[0048] (Nozzle plate (film-like member)) The nozzle plate 112 is a film-like member having ejection ports 112x. The nozzle plate 112 closes the lower end of the liquid holding portion 111 and, together with the liquid holding portion 111, forms a liquid chamber 110S that holds the first solution L1. The ejection ports 112x are in communication with the liquid holding portion 111.

[0049] There are no particular limitations on the planar shape, size in plan view, material, and structure of the nozzle plate 112, and they can be selected appropriately depending on the purpose.

[0050] Examples of the planar shape of the outer edge of the nozzle plate 112 include a circle, an ellipse, a rectangle, a square, a diamond, etc. For example, if the shape of the outer edge of the nozzle plate 112 is a circle, the nozzle plate 112 becomes an annular member.

[0051] If the nozzle plate 112 is too thick, it will be difficult to vibrate, and if it is too thin, the vibration will be difficult to stop, reducing the stability of droplet ejection. Therefore, the thickness of the nozzle plate 112 is preferably 5 μm to 500 μm, and more preferably 20 μm to 100 μm.

[0052] As an example, the nozzle plate 112 may be a circular member having a diameter of 20 mm and an average thickness of 0.05 mm.

[0053] The nozzle plate 112 is not supported at its end on the discharge port 112x side and can vibrate up and down. When the nozzle plate 112 vibrates at its end on the discharge port 112x side, it applies a downward force to the first solution L1 near the discharge port 112x, causing it to be discharged as droplets DR from the discharge port 112x.

[0054] If the nozzle plate 112 is made of a material that is too soft, it will vibrate easily and it will be difficult to immediately stop the vibrations when no ink is being ejected. Therefore, it is preferable to use a material that has a certain degree of hardness.

[0055] Furthermore, when the first solution L1 to be discharged is a dispersion of cells, it is preferable that the material of the nozzle plate 112 is low in cytotoxicity and that cells do not easily adhere to it. As such a material, a highly hydrophilic material is preferable.

[0056] Such materials include, for example, metals, ceramics, and polymeric materials.

[0057] More specifically, examples of the material for the nozzle plate 112 include stainless steel, nickel, aluminum, silicon dioxide, alumina, zirconia, ABS, polycarbonate, fluororesin, etc. Furthermore, a composite material can be used in which the surface of the nozzle plate 112 formed from a material other than the above-mentioned materials is coated with the above-mentioned metal, ceramics, or synthetic phospholipid polymer that mimics a cell membrane (for example, Lipidure manufactured by NOF Corporation).

[0058] There are no particular limitations on the number of the discharge ports 112x arranged, the arrangement pattern, the interval (pitch), the opening shape, the opening size, etc., and these can be selected appropriately depending on the purpose.

[0059] The opening shape of the discharge port 112x can be selected appropriately depending on the purpose. Examples of the opening shape of the discharge port 112x include a circle, an ellipse, a rectangle, etc. Among these, a circle is preferable as the opening shape of the discharge port 112x.

[0060] The average opening diameter of the discharge port 112x is not particularly limited and can be appropriately selected depending on the purpose. When the first solution L1 to be discharged is a dispersion liquid, the opening shape of the discharge port 112x is preferably at least twice the maximum diameter of the dispersoids, in order to prevent the dispersoids, such as cells, dispersed in the first solution L1, from clogging the discharge port 112x.

[0061] When the particle is an animal cell, particularly a human cell, the average opening diameter of the outlet 112x is preferably 10 μm or more and 1000 μm or less.

[0062] The size of human cells varies depending on the cell type, but is generally between 5 μm and 50 μm. Furthermore, when the dispersoid is a cell cluster (spheroid), the size of the cell cluster is several tens of μm to several mm. Therefore, by setting the size of the discharge port 112x as described above and providing the discharge port 112x with an average opening diameter appropriate for the cells to be discharged, clogging of the discharge port can be suppressed.

[0063] It should be noted that while a larger opening diameter of the discharge ports 112x allows relatively large cell aggregates to be discharged, the larger the opening diameter, the more difficult it is to achieve stable discharge. By setting the average opening diameter of the discharge ports 112x to 1000 μm or less, a large number of cell aggregates can be stably discharged. Furthermore, to achieve stable discharge, it is preferable that the upper limit of the average opening diameter of the discharge ports 112x be 200 μm or less.

[0064] Furthermore, the smaller the opening diameter of the discharge port 112x, the more likely shear stress is applied to the cells or cell aggregates passing through the discharge port 112x. Therefore, it is preferable that the average opening diameter of the discharge port 112x is large.

[0065] The position of the discharge ports 112x in the nozzle plate 112 is not particularly limited and can be appropriately selected depending on the purpose. For example, the discharge ports 112x may be located at the center of the nozzle plate 112 when viewed from above, or at a position other than the center of the nozzle plate 112 when viewed from above.

[0066] Furthermore, the number of outlets 112x in the nozzle plate 112 may be one or more. A nozzle plate 112 having multiple outlets 112x can be suitably employed in a cylindrical liquid holding portion 111. In the nozzle plate 112 exposed to the internal space of the liquid holding portion 111, the multiple outlets 112x should be arranged at an equal distance from the central axis of the liquid holding portion 111. By arranging them in this manner, the vibration state of each outlet 112x in the nozzle plate 112 becomes equivalent, and it becomes possible to simultaneously eject droplets from the multiple outlets 112x.

[0067] Note that the nozzle plate 112 having the plurality of ejection ports 112x can be used in liquid holding portions other than cylindrical ones. As long as the vibration state of the nozzle plate 112 at the plurality of ejection ports 112x is equivalent, the nozzle plate 112 can be used in liquid holding portions of various shapes. For example, in the case of an elliptical cylindrical liquid holding portion, if ejection ports are provided at positions that overlap with the focal points in the xy cross section (rectangle) of the liquid holding portion, the vibration state at each ejection port becomes equivalent, and liquid droplets can be ejected simultaneously.

[0068] Similarly, when the liquid holding section is a rectangular tube, an xy cross section of the liquid holding section is assumed, an outlet is provided at an arbitrary point on the cross section, and an outlet is provided at a position that is symmetrical (line symmetric, point symmetric) to the arbitrary point on the cross section, thereby making the vibration state at each outlet equivalent.

[0069] (Excitation member) The vibration member 113 vibrates the nozzle plate 112 based on the input electrical signal, causing droplets DR to be ejected from the ejection ports 112x.

[0070] The vibration member 113 is installed on the upper surface of the nozzle plate 112 .

[0071] There are no particular limitations on the shape, size, material, and structure of the vibration member 113, and they can be selected appropriately depending on the purpose.

[0072] There are no particular limitations on the shape or arrangement of the vibration member 113 as long as it does not impair the effects of the invention, and it can be designed appropriately to match the shape of the nozzle plate 112. For example, if the nozzle plate 112 has a circular planar shape, it is preferable to provide the vibration member 113 concentrically around the discharge port 112x.

[0073] Examples of the vibrating member 113 include a piezoelectric element and an electromagnetic solenoid, with a piezoelectric element being preferred. The piezoelectric element may have a structure in which electrodes for applying a voltage are provided on the upper and lower surfaces of a piezoelectric material, for example. In this case, by applying a voltage between the upper and lower electrodes of the piezoelectric element from the control unit 50, a compressive stress is applied in the lateral direction of the film surface, and the nozzle plate 112 can be vibrated in the vertical direction of the film surface.

[0074] The piezoelectric material is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include lead zirconate titanate (PZT), bismuth iron oxide, metal niobate, barium titanate, or any of these materials to which a metal or a different oxide has been added. Among these, lead zirconate titanate (PZT) is preferred.

[0075] The vibration mode of the piezoelectric element is not particularly limited and can be appropriately selected depending on the purpose, and examples include longitudinal mode, bend mode, etc. A longitudinal mode piezoelectric element is, for example, a stacked type piezoelectric element stacked in the z direction, which expands in the vertical direction (z direction) and contracts in the horizontal directions (x and y directions) when a voltage is applied.

[0076] Furthermore, as a bend mode piezoelectric element, for example, a bimorph type piezoelectric element can be used, in which the piezoelectric element is deformed and bent by applying a voltage, and the position of one end of the piezoelectric element is displaced.

[0077] (fixing member) The fixing member 117 is a cylindrical member that surrounds the periphery of the liquid holding unit 111. The fixing member 117 holds the vibration unit 115 at its lower end. The fixing member 117 is also used to attach the ejection head 110 to the transport unit 120.

[0078] The shape of fixing member 117 is not limited to a cylindrical shape, and various shapes can be adopted as long as it can hold vibration unit 115 and can attach discharge head 110 to transport unit 120.

[0079] When a predetermined electric signal (voltage pulse) is applied to the vibration member 113, the central portion of the vibration member 113, which is not fixed to the fixing member 117, deforms up and down. This deformation applies local pressure to the first solution L1 near the nozzle plate 112 inside the liquid chamber 110S, causing a flow of the first solution L1 toward the discharge port 112x. Part of this flow is discharged as droplets from the discharge port 112x.

[0080] In the manufacturing apparatus 1, the above operation prevents a large pressure from being applied to the entire liquid chamber, as is the case with known inkjet heads having closed liquid chambers. Therefore, when discharging a dispersion liquid in which cells are dispersed, the cells in the dispersion liquid are less likely to be damaged, which is preferable.

[0081] <Transportation section> The transport section 120 includes a first moving section 121 and a second moving section 122 .

[0082] (First moving part) The first moving section 121 has a support member 121a and a linear moving section 121b. The first moving section 121 is a pair of members provided at the end of the second moving section 122 on the +x side and the end of the second moving section 122 on the −x side.

[0083] The support member 121a is a rectangular member when viewed from the +y direction, and supports the second moving part 122.

[0084] The linear moving part 121b is a long member extending in the z direction. The linear moving part 121b moves the support member 121a up and down in the z direction. For example, a known linear actuator equipped with a stepping motor as a drive source can be used as the linear moving part 121b.

[0085] The first moving section 121 moves the support member 121a in the z direction, thereby moving the discharge unit 110L supported by the second moving section 122 in the z direction.

[0086] (Second moving part) The second moving portion 122 has a support member 122a and a linear moving portion 122b.

[0087] The support member 122a is a rectangular member when viewed from the +y direction, and supports the discharge unit 110L.

[0088] The linear moving portion 122b is a long member extending in the x direction. The linear moving portion 122b moves the support member 122a horizontally in the x direction. Both ends of the linear moving portion 122b are supported by the support members 121a of the first moving portion 121, respectively.

[0089] The linear movement portion 122b may be, for example, a known linear actuator equipped with a stepping motor as a drive source.

[0090] The second moving section 122 moves the support member 122a in the x direction, thereby moving the discharge unit 110L supported by the support member 122a in the x direction.

[0091] Reservoir The reservoir 30 is disposed in the ejection direction of the droplets DR and stores the second solution L2. The reservoir 30 is a container that is open upward (in the +z direction). The reservoir 30 may be, for example, a shallow container such as a petri dish or a deep container such as a beaker.

[0092] The material of the reservoir 30 is not particularly limited, and organic materials such as synthetic resins, inorganic materials such as glass, metal materials, and the like can be used as appropriate.

[0093] The storage unit 30 may have a stirring device for stirring the stored second solution L2. This can suppress precipitation and aggregation of the microcapsules MC formed in the second solution L2. A known configuration can be used as the stirring device.

[0094] <<Placement section>> The storage unit 30 is placed on the placement unit 40. The placement unit 40 has an x-stage 41, a y-stage 42, and a base 43.

[0095] The x-stage 41 supports and fixes the storage unit 30. The x-stage 41 also moves the storage unit 30 horizontally in the x direction.

[0096] The y-stage 42 moves the x-stage 41 horizontally in the y direction. The base 43 supports the y-stage 42 .

[0097] The mounting unit 40 can employ a known structure known as an xy stage.

[0098] Control Unit The control unit 50 generates electrical signals to operate each unit of the manufacturing apparatus 1 and supplies them to control each unit. The control unit 50 generates drive signals to be supplied to, for example, the discharge unit 10 and the placement unit 40 and supplies them to each unit to control the operation of each unit.

[0099] <<Position change component>> If microcapsules MC exist at the positions where the droplets DR are dropped in the second solution L2, the microcapsules MC formed from the droplets DR may coalesce with the existing microcapsules MC. In this case, the size (particle diameter) of the resulting microcapsules MC will not be as set, resulting in variations.

[0100] On the other hand, the manufacturing apparatus 1 solves the above problem by including a position changing member. The position changing member has a function of changing the dropping position of the droplets DR on the liquid surface of the second solution L2 in the storage section 30.

[0101] The position changing member 21 shown in FIG. 2 is provided on the fixed member 117 of the discharge head 110, and is a moving member that supports the discharge head 110 and moves the discharge head 110 in the surface direction (x and y directions) of the liquid surface of the second solution L2.

[0102] For example, the position changing member 21 moves the dispensing head 110 in a circular or elliptical motion along a trajectory R around a rotation axis AR.

[0103] For example, when the discharge head 110 moves from the position indicated by the symbol B to the position indicated by the symbol A (case 1) due to the function of the position changing member 21, the discharge opening 112x of the discharge head 110 also moves. At this time, if a droplet DR is discharged from the discharge head 110 while the position of the discharge head 110 is being moved by the position changing member 21, an acceleration in the x and y directions that moves the discharge head 110 from the symbol B to the symbol A is applied to the discharged droplet DR. Therefore, the droplet DR is discharged along an imaginary line AX1 that is inclined with respect to the vertical direction (z direction), and falls into the second solution L2.

[0104] Similarly, when the discharge head 110 moves from the position indicated by the symbol A to the position indicated by the symbol B (case 2), when a droplet DR is discharged from the discharge head 110, an acceleration in the xy directions that moves the discharge head 110 from the symbol A to the symbol B is applied to the discharged droplet DR. Therefore, the droplet DR is discharged along an imaginary line AX2 that is inclined in a direction different from the imaginary line AX1 with respect to the vertical direction (z direction), and falls in a position in the second solution L2 different from that in case 1.

[0105] As a result, the microcapsules MC1 formed in Case 1 and the microcapsules MC2 formed in Case 2 are formed at different positions in the second solution L2.

[0106] There are no particular limitations on the movement of the position changing member 21, as long as it is possible to move the position of the ejection head 110 (the position of the ejection port 112x) in the x and y directions. It is preferable that the movement of the position changing member 21 is a two-dimensional repeated movement (vibration movement) in the x and y directions, such as the circular movement or elliptical movement described above, because this makes it easy to move the ejection head 110 at high speed.

[0107] In the manufacturing apparatus 1, the falling position of the droplets DR in the second solution L2, i.e., the formation position of the microcapsules MC, can be appropriately controlled by appropriately setting the operation of the position changing member 21, the discharge speed of the droplets DR, and the height from the discharge outlet 112x to the liquid surface of the second solution L2.

[0108] 3 is a blower member that blows air toward flying droplets DR. The position change member 22 is provided between the discharge head 110 and the storage unit 30, and blows air W toward the droplets DR discharged from the discharge head 110.

[0109] The position change member 22 may be a known component such as an air nozzle, blower, or fan. There may be only one position change member 22, or there may be multiple position change members 22 with different airflow directions. The position change member 22 may also have a swing function or a louver or other component that changes the airflow direction, thereby changing the airflow direction. A vibrating plate may be provided in the airflow direction of the position change member 22, and the air W sent from the position change member 22 may be made turbulent by vibrating the vibrating plate.

[0110] By blowing air from the position changing member 22 onto the droplets DR, the droplets DR, which would have fallen along the imaginary line AX if there was no position changing member 22, move downwind of the air W sent from the position changing member 22 and fall along the imaginary line AX3. As a result, the microcapsules MC1 that fall and are formed along the imaginary line AX and the microcapsules MC2 that fall and are formed along the imaginary line AX3 are generated at different positions in the second solution L2.

[0111] 4 is an electric field forming member that forms an electric field EF in the space in which the droplets DR fly. The position changing member 23 is a pair of electrodes facing each other along the xy plane between the discharge head 110 and the storage section 30, and can form an electric field in the xy plane direction.

[0112] A plurality of position change members 23 may be provided with the electrodes facing in different directions.

[0113] It is known that the droplets DR ejected from the ejection head 110 are electrically charged. In a preliminary experiment, it was confirmed that when a charged member is brought close to the droplets DR ejected from the ejection head 110, the flying trajectory of the droplets changes due to the influence of the charged member.

[0114] The position changing member 23 may have a charging unit 24 that increases the amount of charge on the droplets DR, provided that the encapsulated substance is not deteriorated and the effects of the invention are not impaired. The charging unit 24 may be a first charging unit 241 that is provided closer to the discharge head 110 than the position changing member 23 and charges the droplets DR. The first charging unit 241 is a pair of electrodes facing each other along the xy plane.

[0115] The charging section 24 may also be a second charging section 242 that charges the discharge head 110. By charging the discharge head 110, the amount of charge on the droplets DR discharged from the discharge head 110 increases.

[0116] In the manufacturing apparatus 1 configured as described above, when droplets DR discharged from the discharge head 110 pass through the electric field EF formed by the position changing member 23, the charged droplets DR are subjected to electrostatic force from the electric field EF formed by the position changing member 23. As a result, the droplets DR, which would have fallen along the imaginary line AX in the absence of the electric field EF, are moved by the electrostatic force received from the electric field EF and fall along the imaginary line AX4. As a result, the microcapsules MC1 that fall and are formed along the imaginary line AX and the microcapsules MC2 that fall and are formed along the imaginary line AX4 are generated at different positions in the second solution L2.

[0117] The above-described position change members 21 to 23 may be used either alone or in combination of two or more.

[0118] As a result, in the manufacturing apparatus 1, it is possible to prevent the droplets DR from being dropped so as to overlap with the microcapsules MC, causing the microcapsules MC to coalesce.

[0119] [Method of manufacturing microcapsules] A method for manufacturing microcapsules can be suitably carried out by using the manufacturing apparatus 1. The method for manufacturing microcapsules includes a step of dropping droplets DR of a first solution L1 ejected from an inkjet ejection head onto a second solution L2 stored in the ejection direction of the droplets DR, thereby forming microcapsules MC covered with a hydrogel film HM.

[0120] As described above, the first solution L1 contains a first substrate, and the second solution L2 contains a second substrate that reacts with the first substrate to form a hydrogel.

[0121] In the step of forming the microcapsules, the droplets DR are dropped while changing the dropping position of the droplets DR on the liquid surface of the second solution L2.

[0122] In the process of forming microcapsules, the dropping position may be changed by changing the position of the ejection head 110 as shown in Fig. 2. Alternatively, the dropping position may be changed by blowing air onto the ejected droplets DR as shown in Fig. 3. Furthermore, as shown in Fig. 4, an electric field EF may be formed in the space through which the ejected droplets DR fly, and the dropping position may be changed by the electrostatic force that the droplets DR receive from the electric field EF.

[0123] The first solution L1 may contain dispersoids that are dispersed in the first solution L1. By using either or both of cells and spheroids as such dispersoids, microcapsules encapsulating cells or spheroids can be produced.

[0124] It should be noted that the apparatus used for carrying out the above-described manufacturing method is not limited to the manufacturing apparatus 1 described above, as long as it is possible to carry out the above-described manufacturing method.

[0125] According to the above-described method for producing microcapsules, it is possible to suppress variations in particle size of the produced microcapsules.

[0126] Furthermore, the microcapsule manufacturing apparatus described above makes it possible to easily manufacture microcapsules whose particle diameters are controlled within a desired range.

[0127] While the preferred embodiments of the present invention have been described above with reference to the accompanying drawings, the present invention is not limited to these examples. The shapes and combinations of the components shown in the above examples are merely examples, and various modifications can be made based on design requirements, etc., without departing from the spirit of the present invention.

[0128] The present invention includes the following aspects.

[0129] [1] A method for manufacturing microcapsules, comprising the step of dropping droplets of a first solution ejected from an inkjet ejection head onto a second solution stored in the ejection direction of the droplets, to form microcapsules covered with a hydrogel membrane, wherein the first solution contains a first substrate, and the second solution contains a second substrate that reacts with the first substrate to form the hydrogel, and in the step of forming the microcapsules, the droplets are dropped while changing their dropping position on the liquid surface of the second solution.

[0130] [2] The method for producing microcapsules according to [1], wherein the position of the ejection head is changed to change the dropping position.

[0131] [3] The method for producing microcapsules according to [1] or [2], wherein the droplet position is changed by blowing air onto the ejected droplets.

[0132] [4] A method for producing microcapsules according to any one of [1] to [3], in which an electric field is formed in the space in which the ejected droplets fly, and the droplet position is changed by the electrostatic force that the droplets receive from the electric field.

[0133] [5] The method for producing microcapsules according to any one of [1] to [4], wherein the first solution contains a dispersoid dispersed in the first solution.

[0134] [6] The method for producing microcapsules according to [5], wherein the dispersoid is either one or both of a cell and a spheroid.

[0135] [7] An apparatus for manufacturing microcapsules covered with a hydrogel membrane obtained by reaction between a first substrate and a second substrate, the apparatus comprising: an ejection head for ejecting droplets of a first solution containing the first substrate; a storage section arranged in the ejection direction of the droplets for storing a second solution containing the second substrate; and a position change member for changing the droplet position on the liquid surface of the second solution in the storage section.

[0136] [8] The microcapsule manufacturing apparatus according to [7], wherein the position changing member is a moving member that moves the ejection head in the direction of the liquid surface.

[0137] [9] The microcapsule manufacturing apparatus according to [7] or [8], wherein the position changing member is a blowing member that blows air onto the flying droplets.

[0138]

[10] The microcapsule manufacturing apparatus according to any one of [7] to [9], wherein the position changing member is an electric field forming member that forms an electric field in the space in which the droplets fly.

[0139]

[11] The microcapsule manufacturing apparatus according to

[10] , further comprising a first charging section that is provided closer to the discharge head than the electric field forming member and charges the droplets.

[0140]

[12] The microcapsule manufacturing apparatus according to

[10] or

[11] , further comprising a second charging unit that charges the ejection head. [Explanation of symbols]

[0141] 1... manufacturing apparatus, 21, 22, 23... position changing member, 24... charging unit, 30... storage unit, 42... y stage, 110, 110a to 110c... ejection head, 241... first charging unit, 242... second charging unit, DR... droplet, EF... electric field, L1... first solution, L2... second solution, MC, MC1, MC2... microcapsules, HM... hydrogel film, W... wind [Prior art documents] [Patent documents]

[0142] [Patent Document 1] Japanese Patent Application Laid-Open No. 2010-201350

Claims

1. a step of dropping droplets of a first solution ejected from an inkjet ejection head onto a second solution stored in the ejection direction of the droplets, thereby forming microcapsules covered with a hydrogel film; the first solution comprises a first substrate; the second solution includes a second substrate that reacts with the first substrate to form the hydrogel; In the step of forming the microcapsules, the droplets are dropped while changing the dropping position of the droplets on the liquid surface of the second solution.

2. The method for producing microcapsules according to claim 1 , wherein the position of the ejection head is changed to change the dropping position.

3. The method for producing microcapsules according to claim 1 or 2, wherein the dropping position is changed by blowing air onto the ejected droplets.

4. 3. The method for producing microcapsules according to claim 1, wherein an electric field is formed in a space in which the ejected droplets fly, and the droplet positions are changed by electrostatic forces acting on the droplets from the electric field.

5. The method for producing microcapsules according to claim 1 or 2, wherein the first solution contains a dispersoid dispersed in the first solution.

6. The method for producing microcapsules according to claim 5 , wherein the dispersoid is either one or both of a cell and a spheroid.

7. An apparatus for producing microcapsules covered with a hydrogel membrane obtained by reacting a first substrate with a second substrate, a discharge head that discharges droplets of a first solution containing the first substrate; a reservoir arranged in a direction in which the droplets are ejected and configured to store a second solution containing the second substrate; a position changing member that changes the droplet position on the liquid surface of the second solution in the storage section.

8. The microcapsule manufacturing device according to claim 7 , wherein the position changing member is a moving member that moves the ejection head in the direction of the liquid surface.

9. 9. The microcapsule manufacturing apparatus according to claim 7, wherein the position changing member is a blower member that blows air onto the flying droplets.

10. 9. The microcapsule manufacturing apparatus according to claim 7, wherein the position changing member is an electric field forming member that forms an electric field in a space in which the droplets fly.

11. The microcapsule manufacturing apparatus according to claim 10, further comprising a first charging section that is provided closer to the discharge head than the electric field forming member and charges the droplets.

12. The microcapsule manufacturing apparatus according to claim 10, further comprising a second charging unit that charges the ejection head.

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