CN106237944B - Core-shell structure preparation method and core-shell structure preparation equipment - Google Patents
Core-shell structure preparation method and core-shell structure preparation equipment Download PDFInfo
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- CN106237944B CN106237944B CN201610212883.1A CN201610212883A CN106237944B CN 106237944 B CN106237944 B CN 106237944B CN 201610212883 A CN201610212883 A CN 201610212883A CN 106237944 B CN106237944 B CN 106237944B
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Abstract
The invention relates to the technical field of core-shell structure preparation, in particular to a core-shell structure preparation method and core-shell structure preparation equipment. The preparation method of the core-shell structure comprises the following steps: a core material liquid titration step: dripping the core material liquid into a generating unit with an action surface, wherein the action surface is a hydrophobic surface so that the core material liquid is singly formed into a spheroid under the action of the action surface or is combined with the formed spheroid in the generating unit under the action of the action surface to be further formed into the spheroid; and shell material liquid titration: and dripping the shell material liquid into the generating unit so that the shell material liquid covers the formed spherical bodies in the generating unit to form a shell layer so as to further form the spherical bodies in the generating unit. The invention skillfully utilizes the hydrophobic characteristic of the action surface to carry out molding treatment on the core material liquid dripped into the generating unit, can realize effective control on the molding shape of the core-shell structure, and ensures that the core-shell structure has better sphericity.
Description
Technical Field
The invention relates to the technical field of core-shell structure preparation, in particular to a core-shell structure preparation method and core-shell structure preparation equipment.
Background
The core-shell structure is a micro-sphere structure with a diameter of 1-1000 μm formed by encapsulating a material such as a solid, a liquid or a gas in a film-forming material, wherein the material loaded inside the core-shell structure is called a core material (or called a core material), and the wall film of the outer encapsulation is called a shell material (or called a wall material). The biological brick (also called biological ink) is a core-shell structure applied to the fields of biological printing (such as the field of 3D biological printing), tissue engineering, regenerative medicine and the like, and biological tissues and organs generated by a biological printing technology are required to have certain biological functions, so the biological brick serving as a biological printing material usually takes a collagen solution containing cells as a core material liquid, and the structures of the biological tissues and the organs are very fine, so the particle size of the biological brick is smaller than that of a common core-shell structure, usually needs to be controlled between 10 and 200 mu m, and the requirement on size precision is very high.
The core-shell structure is still prepared by using the traditional manual preparation process in a biochemical laboratory in the prior art, wherein the most common preparation method is an orifice method. The orifice method generally dissolves a core material liquid and a shell material liquid in the same solution, and then drops the core-shell mixed solution into a curing agent by applying vibration or voltage pulse to a dropping device such as a dropper or an injector containing the core-shell mixed solution, and the core-shell mixed solution is rapidly cured in the curing agent to form a core-shell structure.
Accordingly, the existing core-shell structure manufacturing apparatus, which is also generally based on an orifice method, includes a vibration (or pulse) applying device, a dropping device, and a reaction container disposed below the dropping device, where the reaction container contains a curing agent, the dropping device drops a core-shell mixed solution into the reaction container under the action of the vibration (or pulse) applying device, and the core-shell mixed solution dropped into the reaction container is cured under the action of the curing agent to form a core-shell structure, where the vibration (or pulse) applying device breaks a solution jet to form a droplet with a predetermined particle size by applying oscillation with a certain frequency and a certain amplitude to a flow channel portion of the solution in the dropping device.
The inventor finds that the existing core-shell structure preparation method and preparation instrument have the following problems through analysis and research:
(1) It is difficult to control the molding shape of the core-shell structure. When the core-shell structure is prepared based on the prior art, the core-shell mixed solution is directly dripped into the curing agent for curing, the shape of the core layer and the shape of the shell layer are both formed by respective chemical reaction in the curing process, and the forming shapes of the core layer and the shell layer are not controlled, so that the forming shapes of the core layer and the shell layer are difficult to be effectively controlled, the forming shapes of the core layer and the shell layer are high in randomness, the sphericity of the core layer is poor, and the sphericity of the shell layer coated on the core layer is also poor, so that the forming effect of the finally formed core-shell structure is not ideal. Moreover, since the shape of the core layer is formed by a chemical reaction, the core liquid is required to have a characteristic of being easily molded into a spherical shape, so that the selection range of the core liquid available in the prior art is limited, some materials which are not easily molded into a spherical shape are difficult to be prepared into a core-shell structure meeting the requirements by using the prior art, and the preparation of some core-shell structures is difficult to be realized by using the prior art, so that the development of some specific technical fields is hindered, for example, collagen can be molded under specific conditions, and the core-shell structure is difficult to be directly prepared by using collagen based on the prior art. .
(2) Vibration or pulse liquid separation easily affects the performance of the core-shell structure. In the prior art, liquid separation is performed by a vibration method or a pulse method, and because vibration or voltage pulse can affect the performance of core material liquid and shell material liquid, liquid separation by the vibration method can affect the performance of a core-shell structure, and particularly for the core-shell structure with special performance requirements, such as the core-shell structure with cells with biological activity in the core material, the adverse effect of the vibration or pulse liquid separation method is more prominent.
(3) The prepared core-shell structure has larger grain size. In the prior art, a dropper or an injector is adopted for dripping, the dripping amount is large each time, the size of liquid drops is large, and the particle size of the core-shell structure is directly related to the dripping amount of a solution, so the particle size of the prepared core-shell structure is also large and is usually more than 500 microns, as mentioned above, certain technical fields require the core-shell structure to have a smaller particle size, for example, the particle size of a biological brick is required to be controlled between 10 and 200 microns in the technical field of biological printing, and therefore, the prior art is difficult to meet the requirements of the technical fields such as biological printing and the like on the particle size of the core-shell structure.
(4) The size error of the prepared core-shell structure is large, and the size precision of the core-shell structure is difficult to ensure. In the prior art, a dropper or an injector is adopted to realize the absorption and dripping of the core material liquid and the shell material liquid, on one hand, because the dropper and the injector can not accurately and timely react the solution amount absorbed by the dropper and the injector, the solution absorbed by the dropper and the injector each time can not meet the preparation requirement; on the other hand, the precision of each dripping amount is also difficult to control by a dropper and an injector, so that the size precision of the core-shell structure is difficult to guarantee by the prior art, which not only causes that the actual dripping amount is different from the preset dripping amount in each dripping, the error between the actual particle size of a single core-shell structure and the preset particle size is larger, but also causes that the precision of a plurality of times of repeated component titration processes is difficult to guarantee, the consistency of different dripping amounts cannot be guaranteed, the requirement on the consistency of the particle sizes of different core-shell structures under certain conditions is met, the requirement on the change of different dripping amounts according to the preset difference is difficult to guarantee, and the requirement on the difference of the particle sizes under certain conditions is met, for example, the core-shell structure with a plurality of layers and different thicknesses of shell layers is difficult to prepare based on the prior art.
Therefore, the existing preparation method and preparation instrument of the core-shell structure are difficult to meet the preparation requirements of the core-shell structure comprising the biological brick and the like, have the defects of poor forming shape, larger particle size, poorer size precision, lower efficiency and the like, and also have the problem of easily damaging the cell activity of the biological brick.
Disclosure of Invention
The invention aims to solve the technical problems that: the existing preparation method of the core-shell structure is difficult to control the forming shape of the core-shell structure.
In order to solve the technical problems, the invention provides a core-shell structure preparation method and core-shell structure preparation equipment.
According to a first aspect of the present invention, there is provided a method for preparing a core-shell structure, comprising the steps of:
a core material liquid titration step: dripping the core material liquid into a generating unit with an action surface, wherein the action surface is a hydrophobic surface so that the core material liquid is singly formed into a spheroid under the action of the action surface or is combined with the formed spheroid in the generating unit under the action of the action surface to be further formed into the spheroid; and the combination of (a) and (b),
shell material liquid titration: and dripping the shell material liquid into the generating unit to coat the shell material liquid on the formed spherical bodies in the generating unit to form a shell layer, and further forming the spherical bodies in the generating unit.
Optionally, in the shell liquid titration step, the shell liquid coats the spheroids molded in the production unit on the action surface to further form the spheroids.
Optionally, the preparation method of the core-shell structure further comprises a pretreatment step, wherein the pretreatment step is used for carrying out pretreatment on the core material liquid and/or the shell material liquid so that the core material liquid or the shell material liquid can be combined with the formed spheroids in the generation unit.
Optionally, in the pre-treatment step, the core material liquid and/or the shell material liquid and the formed spheroids in the generation unit are charged differently to combine the core material liquid or the shell material liquid with the formed spheroids in the generation unit.
Optionally, in the pretreatment step, a step of adjusting the pH of the core material liquid or the shell material liquid is further included.
Optionally, in the step of adjusting the pH of the core material liquid, the pH of the core material liquid is adjusted to 6 to 10.
Optionally, the core-shell structure preparation method further includes:
solidifying the core material liquid: setting between the core material liquid titration step and the shell material liquid titration step, and curing the spheroids formed in the core material liquid titration step;
and/or the presence of a gas in the gas,
shell material liquid curing step: after the shell material liquid titration step, the shell layer formed in the shell material liquid titration step is subjected to a curing treatment.
Optionally, the curing treatment includes dropping a curing agent to effect curing or includes controlling a temperature to effect curing.
Optionally, the curing treatment comprises controlling the temperature to achieve curing, the temperature being controlled to be 20-40 ° for 5-180 minutes.
Optionally, repeating the core liquid titration step at least twice to form spheroids having at least two core layers; and/or repeating the shell material liquid titration step at least twice to form spheroids having at least two shell layers.
Optionally, the preparation method of the core-shell structure further comprises a shell droplet quantitative determination step: and determining the dropping amount of the shell material liquid in the shell material liquid titration step.
Optionally, the core-shell structure preparation method further comprises a raffinate removal step: and (4) removing residual liquid in the generating unit after the shell material liquid titration step.
Alternatively, in the residual liquid removing step, a cleaning liquid is first dropped into the generation unit to clean the residual shell material liquid in the generation unit, and then the cleaning liquid is discharged out of the generation unit together with the residual shell material liquid.
Optionally, the shell liquid titration step comprises: and shaking the generation unit in the process that the formed spherical bodies in the generation unit are coated with the shell material liquid to ensure that the formed spherical bodies in the generation unit are uniformly coated with the shell material liquid.
Optionally, the preparation method of the core-shell structure further comprises temperature control of the core material liquid and the shell material liquid.
Optionally, in the step of titrating the nuclear material liquid, dispersing the nuclear material liquid into liquid drops with preset particle size by using compressed air, and dropping the liquid drops into the generating unit; and/or in the shell material liquid titration step, dispersing the shell material liquid into liquid drops with preset particle sizes by using compressed air, and dripping the liquid drops into the generation unit.
Optionally, the hydrophobic surface is a superhydrophobic surface.
The invention provides a preparation device of a core-shell structure, which comprises a liquid dropping device and a generation device, wherein the generation device comprises at least one generation unit, the generation unit is provided with an action surface, the action surface is a hydrophobic surface, the liquid dropping device is used for dropping core material liquid and/or shell material liquid into the generation unit, the action surface enables the core material liquid to be singly molded into a spheroid or enables the core material liquid to be combined with the spheroid molded in the generation unit to be further molded into the spheroid, and the shell material liquid covers the spheroid molded in the generation unit to form a shell layer and further forms the spheroid in the generation unit.
Optionally, the active surface is planar, or the active surface comprises an undercut curved surface portion.
Optionally, the generating unit is a flat plate, and the acting surface is a plate surface of the flat plate; alternatively, the generating unit is an open-topped chamber, the bottom wall of the chamber is planar or comprises a concave curved surface portion, and the active surface is the bottom wall of the chamber.
Optionally, the concave curved surface portion is U-shaped or spherical crown shaped.
Optionally, the generating device comprises at least two generating units, the at least two generating units being arranged on the generating device in isolation from each other.
Optionally, the core-shell structure preparation equipment further comprises a shaking device, and the shaking device is used for enabling the generation unit to shake so that the core material liquid or the shell material liquid can be uniformly coated on the formed spherical bodies in the generation unit in the process that the core material liquid or the shell material liquid coats the formed spherical bodies in the generation unit.
Optionally, the generating device further comprises a liquid discharging structure for discharging the residual liquid in the generating unit after the core-shell structure is formed.
Optionally, the generating unit is a chamber with an open top end, and a bottom wall of the chamber is the active surface, wherein the drainage structure is arranged on the bottom wall of the chamber; alternatively, the drainage structures are provided on the side walls of the chamber.
Optionally, the liquid discharge structure is disposed on a side wall of the chamber, and the core-shell structure preparation apparatus further includes an inclination control device for controlling the generation unit to incline toward the side wall of the chamber where the liquid discharge structure is disposed when the remaining liquid in the generation unit after the core-shell structure is formed is discharged.
Optionally, the drain structure comprises a drain hole in communication with the generation unit.
Optionally, the drainage structure further comprises a blocking piece for blocking the drainage hole, and the blocking piece is detachably connected with the drainage hole.
Optionally, the dropping device comprises a liquid separating device and at least one suction head, the suction head can suck the nuclear material liquid and/or the shell material liquid, the liquid separating device comprises a compressed air filling part and at least one suction head mounting part for mounting the suction head, and the compressed air filling part fills the compressed air into the suction head through the suction head mounting part so as to disperse the nuclear material liquid or the shell material liquid in the suction head into liquid drops with preset particle sizes to be dropped into the generating unit.
Optionally, at least a portion of the inner wall of the tip at the dropping end for dropping the core material liquid and/or the shell material liquid is a hydrophobic surface.
Optionally, the dropping device further includes a suction amount detecting section for detecting a suction amount of the core material liquid or the shell material liquid sucked by the tip.
Optionally, the uptake of core material liquid and/or shell material liquid is adjustable.
Optionally, the dropping device comprises at least two tips, at least one of the at least two tips is used for sucking the core material liquid, and at least one of the at least two tips is used for sucking the shell material liquid.
Optionally, the separating device comprises at least two suction head mounting parts, and the distance between the at least two suction head mounting parts can be adjusted.
Optionally, the cleaner head is removably mounted to the cleaner head mounting portion.
Optionally, the core-shell structure preparation equipment further comprises a suction head storage module, and the suction head storage module is used for storing suction heads.
Optionally, the core-shell structure preparation equipment further comprises a displacement driving device, and the displacement driving device is used for controlling the relative movement of the liquid dropping device and the generating unit.
Optionally, the core-shell structure preparation equipment further comprises a liquid storage device, the liquid storage device at least comprises a first liquid storage space and a second liquid storage space, the first liquid storage space is used for storing core material liquid, and the second liquid storage space is used for storing shell material liquid.
Optionally, the liquid storage device further comprises a third liquid storage space for storing the cleaning liquid; and/or the liquid storage device further comprises a fourth liquid storage space, and the fourth liquid storage space is used for storing the curing agent.
Optionally, the core-shell structure preparation equipment further comprises a temperature control module, and the temperature control module is used for controlling the temperature of the core material liquid and/or the shell material liquid.
Optionally, the temperature control module comprises a first temperature control module, and the first temperature control module is used for controlling the temperature of the generation unit so that the temperature of the generation unit can be consistent with the temperature required by the core material liquid and/or the shell material liquid; and/or the core-shell structure preparation equipment further comprises a liquid storage device, the liquid storage device at least comprises a first liquid storage space and a second liquid storage space, the first liquid storage space is used for storing nuclear material liquid, the second liquid storage space is used for storing shell material liquid, the temperature control module comprises a second temperature control module, and the second temperature control module is used for controlling the temperature of the liquid storage device so that the temperature of the liquid storage device can be consistent with the temperature required by the nuclear material liquid and/or the shell material liquid.
Optionally, the core-shell structure preparation equipment further comprises a material pretreatment device, and the material pretreatment device is used for performing pretreatment on the core material liquid and/or the shell material liquid, so that the core material liquid or the shell material liquid can be combined with the formed spherical bodies in the generation unit.
Optionally, the material pre-treatment device is configured to charge the core material liquid and/or the shell material liquid oppositely to the formed spheroids in the generating unit.
Optionally, the core-shell structure preparation equipment is bioactive microsphere preparation equipment.
Optionally, the hydrophobic surface is a superhydrophobic surface.
The core-shell structure preparation method is different from an orifice method in the prior art, and is characterized in that the core material liquid dripped into the generation unit is molded by utilizing the hydrophobic characteristic of the action surface to form the core material liquid into a spheroid, so that the sphericity of a core layer can be ensured, the spheroid can be more uniformly wrapped by the shell material liquid, and the spheroid can be completely wrapped by the shell material liquid, and the finally prepared core-shell structure has better sphericity.
Other features of the present invention and advantages thereof will become apparent from the following detailed description of exemplary embodiments of the invention, which proceeds with reference to the accompanying drawings.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.
Fig. 1a shows a schematic view of the shape of a drop of liquid on a hydrophilic surface.
FIG. 1b shows a schematic view of the shape of the drop on a hydrophobic surface.
Fig. 2 shows a schematic structural diagram of core-shell structure manufacturing equipment according to a first embodiment of the present invention.
Fig. 3 shows a plan view of the perforated plate as a generating device in the exemplary embodiment shown in fig. 2.
Fig. 4 shows a schematic view of the structure of the blind hole when the bottom wall is U-shaped, and shows a schematic view of a process of forming spheroids of different preset particle diameters by dropping liquids to be reacted with different volumes based on the blind hole.
Fig. 5 shows a schematic structural diagram of a blind hole when the bottom wall is a plane, and shows a schematic diagram of a process for forming spheroids with different preset particle diameters by dropping different volumes of reaction liquids to be reacted based on the blind hole.
Fig. 6 shows a core-shell structure with a single core layer and a double shell layer.
Fig. 7 shows a core-shell structure with a double core layer and a single shell layer.
Fig. 8 shows a core-shell structure with a double-layer core layer and a double-layer shell layer.
In the figure:
1. a liquid dropping device; 11. a liquid separating device; 12. a suction head;
2. an orifice plate; 21. blind holes; 211. an active surface;
3. a suction head storage module;
43. an XYZ motion module;
51. a first temperature control module; 511. a vapor chamber; 52. a second temperature control module;
6. a liquid storage device; 61. a first reservoir space; 62. a second reservoir space;
7. a base; 71. a first base plate; 72. a second base plate;
8. a support frame;
9. and a control device.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of protection of the present invention.
Techniques, methods, and apparatus known to those of ordinary skill in the relevant art may not be discussed in detail but are intended to be part of the specification where appropriate.
In the description of the present invention, it is to be understood that the orientation or positional relationship indicated by the orientation words such as "front, rear, upper, lower, left, right", "lateral, vertical, horizontal" and "top, bottom", etc. are usually based on the orientation or positional relationship shown in the drawings, and are only for convenience of description and simplicity of description, and in the case of not making a reverse description, these orientation words do not indicate and imply that the device or element being referred to must have a specific orientation or be constructed and operated in a specific orientation, and therefore, should not be considered as limiting the scope of the present invention; the terms "inner and outer" refer to the inner and outer relative to the profile of the respective component itself.
In the description of the present invention, it should be understood that the terms "first", "second", etc. are used to define the components, and are used only for the convenience of distinguishing the corresponding components, and if not otherwise stated, the terms have no special meaning, and thus, should not be construed as limiting the scope of the present invention.
In the description of the present invention, the "core-shell structure" refers to a structure in which a solid, liquid or gas is encapsulated with a film-forming material, wherein a material for forming a core layer is referred to as a core material, and a material for forming a shell layer of an outer encapsulation is referred to as a shell material.
As used herein, the term "bio-brick" is used to refer to a basic unit constructed by the method of the present invention that can be used in a variety of fields, such as bioprinting (e.g., 3D bioprinting), tissue engineering, regenerative medicine, and the like. Preferably, the bio-brick of the present invention may have a structure and composition of: a nuclear layer comprising cells, wherein the cells are capable of growing, proliferating, differentiating or migrating, the nuclear layer being made of a biodegradable material and providing a substance required for the vital movement of the cells; and a shell layer which is used for encapsulating the core layer, is positioned at the outer side, is made of biodegradable materials and provides mechanical protection for the core layer and cells at the inner part, and the biological brick with the preferable structure can be used as a basic unit for biological 3D printing. The core-shell structure prepared by the preparation method of the core-shell structure is represented as a bioactive microsphere.
In certain embodiments of the invention, the core layer of the bio-brick encapsulates one or more cells, such as one or more cells, e.g., 1-10 6 Individual cells, e.g. 1-10 5 、1-10 4 1-5000, 1-2000, 10-900, 20-800, 30-700, 40-600, 50-500, 60-400, 70-300, 80-200, 10-100 cells.
In certain preferred embodiments, the core-shell structures (e.g., biobricks) produced by the methods of the present invention are solid or semi-solid. In certain other preferred embodiments, the core-shell structures (e.g., biobricks) produced by the methods of the present invention are in a gel state, e.g., the core layer and/or the shell layer of the core-shell structures (e.g., biobricks) produced by the methods of the present invention can be in a gel state. In certain preferred embodiments, the core-shell structures (e.g., biobricks) produced by the methods of the present invention comprise a hydrogel. In certain preferred embodiments, the hydrogel comprises alginate, agarose, gelatin, chitosan, or other water-soluble or hydrophilic polymers.
The invention provides a preparation method of a core-shell structure, which comprises the following steps:
a core material liquid titration step: dripping the core material liquid into a generating unit with an action surface 211, wherein the action surface 211 is a hydrophobic surface so that the core material liquid is singly molded into a spheroid under the action of the action surface 211 or is combined with the formed spheroid in the generating unit under the action of the action surface 211 to be further molded into a spheroid; and
shell material liquid titration: and dripping the shell material liquid into the generation unit to ensure that the shell material liquid is coated on the formed spherical body in the generation unit to form a shell layer, and further forming a spherical body shell material liquid titration step in the generation unit.
After the liquid is dripped into the solid surface, an included angle between a tangent line of a gas-liquid interface passing through a solid-liquid-gas intersection point and a solid-liquid boundary line is a contact angle, the larger the contact angle is, the stronger the hydrophobicity of the solid surface is, and the liquid dripped into the solid surface is easier to form a sphere. According to the difference of the contact angle, the solid surface can be divided into a hydrophilic surface, a hydrophobic surface and a super-hydrophobic surface, wherein the hydrophilic surface refers to the solid surface with the contact angle smaller than 90 degrees, as shown in fig. 1a, when liquid is dropped into the hydrophilic surface, the liquid cannot be formed into a spherical shape, but rather lies on the solid surface and is flat; the hydrophobic surface refers to a solid surface having a contact angle of more than 90 °, and the superhydrophobic surface refers to a solid surface having a contact angle of more than 150 ° and a rolling angle of less than 10 °, which is shaped like a sphere or an ellipsoid when a liquid is dropped onto the hydrophobic surface, as shown in fig. 1 b.
Different from the orifice method in the prior art, the core-shell structure preparation method skillfully utilizes the hydrophobic characteristic of the action surface 211 to carry out forming treatment on the core material liquid dripped into the generation unit, so that the core material liquid is formed into a spheroid, the sphericity of a core layer can be ensured, the spheroid can be more uniformly wrapped by the shell material liquid, and the spheroid can be completely wrapped by the shell material liquid, and therefore, the finally prepared core-shell structure has better sphericity.
Spheroids according to the invention are not only spheres but also ellipsoids and may also include other spheroids that approximate a sphere or ellipsoid. Based on the core-shell structure preparation method, the core-shell structure with a single-layer core layer and a single-layer shell layer can be prepared, and in this case, in the core material liquid titration step, the core material liquid is independently formed into a spheroid under the action of the action surface 211 to form the single-layer core layer; in the shell material liquid titration step, the shell material liquid wraps a single-layer core layer (the single-layer core layer is the spheroid formed in the generating unit under the condition) to form a single-layer shell layer, and finally a core-shell structure with the single-layer core layer and the single-layer shell layer is formed. Moreover, based on the core-shell structure preparation method of the present invention, a core-shell structure having multiple core layers can also be prepared, wherein the core-shell structure has at least two core layers, in this case, in the core material liquid titration step of the present invention, the core material liquid is combined with the formed spheroids in the generation unit under the action of the action surface 211 to further form spheroids, and the formed spheroids in the generation unit can be at least one formed core layer; or a core-shell combination having at least one shell layer. Similarly, based on the core-shell structure preparation method of the present invention, a core-shell structure having multiple shell layers may also be prepared, where such core-shell structure has at least two shell layers, and in this case, in the shell material liquid titration step, the object coated with the shell material liquid (i.e., the formed spheroid in the generating unit) may be a formed core-shell conjugate having at least one shell layer.
In order to obtain a plurality of core layers, the core-shell structure preparation method of the invention can repeat the step of titrating the core material liquid at least twice before the step of titrating the shell material liquid, so that a spheroid with at least two core layers can be formed, wherein each core layer can be the same or different core materials; similarly, in order to obtain multiple shell layers, the core-shell structure preparation method of the present invention may repeat the shell material liquid titration step at least twice after the core material liquid titration step, so that a spheroid having at least two shell layers may be formed, wherein each shell layer may be the same or different shell materials.
Therefore, the preparation method of the core-shell structure can be used for preparing the core-shell structure with the single-layer core layer and the single-layer shell layer and also can be used for preparing the core-shell structure with the multiple-layer core layer and/or the multiple-layer shell layer, so that the requirements on various core-shell structures in practice can be met.
In addition, based on the core-shell structure preparation method, the molding of the core layer and the shell layer does not depend on the chemical reaction of the core layer and the shell layer, so that the core-shell structure preparation method is not only suitable for the core material liquid which is easy to mold, but also suitable for the core material liquid which is difficult to mold, and therefore the core-shell structure preparation method can effectively expand the selection range of the available core material liquid, the preparation of the core-shell structures such as biological bricks and the like is not limited by the molding performance of the core material liquid, and the core-shell structure preparation method has important significance for the development of the technical fields such as biological printing and the like.
In the present invention, the hydrophobic surface is preferably a superhydrophobic surface, so that the action surface 211 can further improve the sphericity of the spheroids formed by the core material liquid, and ultimately further improve the sphericity of the core-shell structure produced.
In the shell material liquid titration step of the present invention, the shell material liquid preferably coats the spheroids on the action surface 211, so that the action surface 211 can also perform a certain molding effect on the shell material liquid, on one hand, the shell material liquid can more sufficiently and uniformly coat the formed spheroids in the generation unit, and on the other hand, the sphericity of the formed shell layer can also be improved, thereby further improving the sphericity of the finally prepared core-shell structure.
In the step of titrating the nuclear material liquid, the nuclear material liquid can be dispersed into liquid drops with preset particle sizes by using compressed air and then dripped into the generating unit; in the shell material liquid titration step of the present invention, the shell material liquid may be dispersed into droplets having a predetermined particle diameter by using compressed air and dropped into the generation unit. By adopting the compressed air liquid separation method, the core material liquid and the shell material liquid do not need to be vibrated, and the influence on the performance of the core material liquid and the shell material liquid is small, so that the problem that the core-shell structure performance is damaged due to liquid separation by adopting a vibration or pulse applying device in the prior art can be effectively solved, particularly for the core material liquid such as collagen containing cells inside, the damage to the cell activity can be obviously reduced by adopting the compressed air liquid separation mode, and the requirement of the biological printing field on the biological activity of the core-shell structure can be met. Moreover, by adopting a compressed air liquid separation mode, the core-shell structure preparation method disclosed by the invention can be used for preparing the core-shell structure with smaller particle size, can meet the requirements of the field of biological printing on the particle size, can accurately control the amount of the solution sucked in real time, can more accurately control the precision of the dripping amount each time, effectively reduces the size error, and can meet the requirements on the consistency of the particle size and the difference of the particle size.
In order to make the shell material liquid more easily coat the spheroids, the method for preparing the core-shell structure of the invention may further include a pretreatment step before the core material liquid titration step, wherein the pretreatment step enables the core material liquid or the shell material liquid to be combined with the spheroids formed in the generation unit. In the pretreatment step, the core material liquid or the shell material liquid and the formed spherical bodies in the generation unit can be charged differently, so that the core material liquid or the shell material liquid and the formed spherical bodies in the generation unit can be combined with each other by electrostatic adsorption. In order to further improve the electrostatic adsorption effect, the pretreatment step also comprises a step of adjusting the pH value of the core material liquid or the shell material liquid, and the pH value of the core material liquid or the shell material liquid is adjusted, so that more charges participating in electrostatic adsorption in the core material liquid or the shell material liquid can be obtained, the electrostatic adsorption reaction is more violent, and the core material liquid or the shell material liquid can fully coat the whole spherical body. Of course, the pretreatment step may also adopt other methods to combine the core material liquid or the shell material liquid with the formed spheroids in the generating unit, besides the electrostatic adsorption method, where the combination may be that all substances in the shell material liquid or the core material liquid are combined with the formed spheroids in the generating unit, or that some substances in the shell material liquid or the core material liquid are combined with the formed spheroids in the generating unit.
It should be noted that, in the shell material liquid titration step, the dropping amount of the shell material liquid can be determined in a pre-calculation manner to realize quantitative titration on the shell material liquid as required, and based on this, the shell material liquid dropping amount determination step can be set in the core-shell structure preparation method of the present invention, specifically, the dropping amount of the shell material liquid can be estimated and determined in advance according to parameters such as the volume, the thickness, and the electric charge amount of the core layer, so that the dropped shell material liquid amount just meets the use requirement. However, as an alternative embodiment, in the shell material liquid titration step of the present invention, an excessive amount of shell material liquid may be dropped into the generation unit first, and then the residual liquid in the generation unit after the shell material liquid titration step is discharged through the residual liquid removal step, so that the problem that the dropping amount of the shell material liquid is still inaccurate due to the fact that the parameters such as the volume, the thickness, and the electric charge of the core layer are not easily determined or the determined parameters are easily deviated can be effectively avoided, and it is ensured that the dropping amount of the shell material liquid can meet the use requirements. Preferably, in the residual liquid cleaning step, firstly, a cleaning solution is dropped into the generating unit to clean the residual shell material liquid in the generating unit, the cleaning solution is used to remove the redundant charged substances in the shell material liquid, so as to prevent the redundant charged shell material liquid from forming a non-uniform structure or a convex structure on the surface of the spheroid and influencing the molding shape and the physical and chemical properties of the core-shell structure, and then the cleaning solution and the residual shell material liquid (i.e. the redundant shell material liquid which is not combined with the spheroid) are discharged out of the generating unit together.
In addition, in order to coat the spherical body with the shell material liquid more uniformly, in the shell material liquid titration step of the invention, the generation unit can be shaken in the process of coating the spherical body with the shell material liquid, and the spherical body in the generation unit is coated with the shell material liquid uniformly by shaking. The shaking can be applied here either manually or by means of a shaking device. In addition, some liquid used for preparing the core-shell structure has certain requirements on temperature, for example, the core material liquid of the biological brick containing cells inside can ensure the activity of the cells inside, so in order to meet the requirements of the core-shell structure on temperature, the preparation method of the core-shell structure can control the temperature of the core material liquid and/or the shell material liquid in the preparation process.
The preparation method of the core-shell structure can also comprise a core material liquid curing step and/or a shell material liquid curing step, wherein the core material liquid curing step is arranged between the core material liquid titration step and the shell material liquid titration step, and the spheroids formed in the core material liquid titration step are cured; the shell material liquid curing step is arranged after the shell material liquid titration step, and the shell layer formed in the shell material liquid titration step is cured, namely the core material liquid curing step and the shell material liquid curing step are respectively used for curing the core layer and the shell layer. The curing treatment of the invention can realize curing by dripping the curing agent into the generating unit, namely, a curing agent curing mode, but because the forming is not realized by the chemical reaction in dripping the curing agent, the curing treatment of the invention is not limited to the curing agent curing mode, and can also realize curing by controlling the temperature, namely, a temperature control curing mode. Compared with the orifice method in the prior art, the curing mode available in the preparation method of the core-shell structure is more various and flexible.
According to a second aspect of the present invention, the present invention also provides a core-shell structure preparation apparatus. Fig. 2 to 5 respectively show schematic structural diagrams of core-shell structure manufacturing equipment according to two embodiments of the present invention. Referring to fig. 2 to 5, the core-shell structure preparation apparatus provided by the present invention includes a dropping device 1 and a generating device, wherein the generating device includes at least one generating unit, the generating unit has an acting surface 211, the acting surface 211 is a hydrophobic surface, the dropping device 1 is configured to drop a core material liquid and/or a shell material liquid into the generating unit, and the acting surface 211 enables the core material liquid to be formed into a spheroid alone or enables the core material liquid to be combined with the spheroid formed in the generating unit to further form a spheroid, and the shell material liquid covers the spheroid formed in the generating unit to form a shell layer so as to further form a spheroid in the generating unit.
The core-shell structure preparation equipment provided by the invention skillfully utilizes the characteristic of the hydrophobic surface, and the action surface 211 of the generation unit is set as the hydrophobic surface, so that the core material liquid firstly dripped into the generation unit by the dripping device 1 can be formed into a spherical or ellipsoidal shape to form a spheroid with good sphericity, the shell solution later dripped into the generation unit can be conveniently and uniformly and predictably wrapped, and the shell material liquid can completely wrap the spheroid to form a core-shell structure with good sphericity. Therefore, the core-shell structure preparation equipment provided by the invention can control the sphericity of the spherical body by utilizing the hydrophobic characteristic of the action surface 211, and can realize control on the core-shell structure forming shape, so that the core-shell structure has better sphericity. Moreover, when the spherical body is wrapped by the shell liquid on the action surface 211, the action surface 211 can also play a certain role in molding the shell liquid, so that the sphericity of the core-shell structure can be further improved.
The action surface of the present invention may be a plane, for example, the generating unit is a flat plate, and the action surface 211 is a plate surface of the flat plate; alternatively, the generating unit is an open-topped chamber (e.g., a beaker), and the bottom wall of the chamber is planar and the active surface 211 is the bottom wall of the chamber. In this case, the core-shell structure preparation apparatus controls the molding shape of the core-shell structure using the hydrophobic or superhydrophobic characteristic of the action surface 211.
Preferably, however, the active surface 211 of the present invention comprises a concave curved surface, for example, the generating unit is an open-topped chamber (e.g., a beaker), and the bottom wall of the chamber comprises a concave curved surface, the active surface 211 being the bottom wall of the chamber. Because concave curved surface portion can produce the guide effect that makes nuclear material liquid and shell material liquid assemble to the center, not only can make nuclear material liquid and shell material liquid shape for globular or ellipsoid form more easily like this, make the nucleocapsid structure have better sphericity, moreover, make shell material liquid assemble to the center and can also make nuclear material liquid and/or shell material liquid more fast and fully cladding on the spheroid, improve parcel efficiency to further improve the parcel effect. Therefore, in this case, the core-shell structure preparation equipment can not only control the forming shape of the core-shell structure by using the hydrophobic characteristic of the action surface 211, but also further improve the sphericity of the core-shell structure by using the convergence and guide action of the concave curved surface portion, and further improve the efficiency of wrapping the spherical body by the core material liquid and/or the shell material liquid. More preferably, the concave curved surface portion is U-shaped or spherical crown shaped.
The number of the generating units can be one or at least two, but in order to further improve the preparation efficiency, the number of the generating units is preferably at least two, and the at least two generating units are arranged on the generating device in an isolated mode, so that the core-shell structure preparation equipment can simultaneously complete the preparation of a plurality of core-shell structures, the preparation time can be saved, and the preparation efficiency can be improved. In addition, the generation units are isolated from each other, and the independence of the preparation process of each core-shell structure can be ensured, so that on one hand, compared with the condition that a plurality of core-shell structures are prepared in the same generation unit at the same time, the preparation of each core-shell structure is not interfered with each other, the performance of each core-shell structure can be ensured not to be influenced by other core-shell structures; on the other hand, the preparation processes of the core-shell structures are mutually independent, as shown in fig. 4 and 5, simultaneous preparation of core-shell structures with different particle sizes can be conveniently realized by controlling different dripping amounts in each generating unit, and even simultaneous preparation of different types of core-shell structures can be realized by dripping different core material liquids or shell material liquids in each generating unit, so that the core-shell structure preparation equipment disclosed by the invention can meet more various preparation requirements; on the other hand, as the generation units are isolated from each other, even if the generation device is shaken, the generation units do not interfere with each other, so that the spherical body can be coated with the shell material liquid more uniformly by shaking the generation units in the process of coating the spherical body with the shell material liquid, and the shaking can be manually shaken by an operator.
After the core-shell structure is prepared, residual liquid possibly exists in the generating unit, such as redundant shell material liquid, cleaning liquid or curing agent and the like, certainly, sponge or other similar water absorbing substances can be used for discharging the residual liquid, but in order to enable the residual liquid to be discharged more cleanly and enable the residual liquid to be processed more conveniently, the residual liquid is preferably discharged through arranging the liquid discharging structure. When the generating unit is the cavity with the top end opened, and the acting surface 211 is the bottom wall of the cavity, the liquid discharge structure can be arranged on the bottom wall of the cavity, or the liquid discharge structure can also be arranged on the side wall of the cavity, in this case, an inclination control device can be arranged, and the inclination control device is used for controlling the generating unit to incline towards the side wall of the cavity, which is provided with the liquid discharge structure, of the side wall when residual liquid in the generating unit after the core-shell structure is formed needs to be discharged, so that convenient discharge of redundant solution can be ensured, influence on preparation of the core-shell structure due to arrangement of the liquid discharge structure can be avoided, and especially influence on the forming effect of the nuclear material liquid on the acting surface 211 due to the liquid discharge structure can be avoided.
In order to avoid the problem of damaging the core-shell structure performance caused by liquid separation by adopting a vibration or pulse applying device in the prior art, the liquid dropping device 1 of the invention can comprise a liquid separating device 11 and at least one suction head 12, wherein the suction head 12 can suck core material liquid and/or shell material liquid, the liquid separating device 11 comprises a compressed air filling part and at least one suction head mounting part for mounting the suction head 12, and the compressed air filling part fills compressed air into the suction head 12 through the suction head mounting part so as to disperse the core material liquid or the shell material liquid in the suction head 12 into liquid drops with preset particle sizes to be dropped into the generating unit. According to the liquid separating device 11 of the liquid dropping device 1, the core material liquid or the shell material liquid is dispersed into liquid drops with preset particle sizes through compressed air, and the compressed air liquid separating method is realized. Moreover, by adopting the liquid separating device 11 with the compressed air charging part, the core-shell structure preparation equipment can prepare the core-shell structure with smaller particle size, can meet the requirement of the biological printing field on the particle size, can accurately control the amount of the solution sucked in real time, can more accurately control the precision of the dripping amount each time, effectively reduces the size error, can meet the requirement on the consistency of the particle size and the difference of the particle size.
The dripping device 1 according to the invention comprises at least one suction nozzle 12, i.e. the dripping device 1 may comprise one suction nozzle 12 or at least two suction nozzles 12. Wherein, to the condition that dropping liquid device 1 only includes a suction head 12, this suction head 12 both is used for absorbing nuclear material liquid, be used for absorbing shell material liquid again, it also needs successively to absorb nuclear material liquid and shell material liquid promptly, under this kind of condition, in order to avoid nuclear material liquid and shell material liquid's mutual interference, after accomplishing nuclear material liquid titration and before beginning to absorb shell material liquid, need clear away the interior remaining nuclear material liquid of suction head 12 through modes such as washing suction head 12, this not only can lead to the preparation process comparatively complicated, also can lead to preparation efficiency to be lower. In order to solve the problem, the dropping device 1 of the present invention preferably includes at least two suction heads 12, at least one of the at least two suction heads 12 is used for sucking the core material liquid, and at least one of the at least two suction heads 12 is used for sucking the shell material liquid, that is, different suction heads 12 are used for sucking the core material liquid and the shell material liquid, so as to effectively avoid the mutual interference of the core material liquid and the shell material liquid, and to omit the cleaning step of the suction heads 12 after completing the titration of the core material liquid and before starting to suck the shell material liquid, thereby effectively simplifying the operation steps of preparing the core-shell structure by using the core-shell structure preparation equipment, and improving the preparation efficiency. More preferably, the dropping device 1 comprises a plurality of suction heads 12, wherein a part of the suction heads 12 is used for sucking the core material liquid, and another part of the suction heads 12 is used for sucking the shell material liquid, and when other solutions such as cleaning liquid and the like need to be used in the preparation process, a separate part of the suction heads 12 can be used for sucking other solutions such as cleaning liquid and the like, so that each solution is sucked by the special suction head 12, the mutual interference among different solutions is avoided, the cleaning frequency of the suction heads 12 in the preparation process can be reduced, and the preparation efficiency is improved.
In order to make the suction amount of the suction head 12 more accurate, the dropping device 1 of the present invention further comprises a suction amount detecting portion, which can detect the amount of the core material liquid or the shell material liquid sucked by the suction head 12, so as to ensure that the amount of the sucked solution meets the preparation requirement, and to avoid the influence of too little or too much suction amount on the smooth operation of the core-shell structure preparation process. In order to obtain a core-shell structure with a smaller particle size, the tip 12 of the present invention may also have a tip structure such as a long capillary glass tube or a steel needle with an inner diameter of 130 μm, and the tip 12 having such a tip structure can drop droplets of several tens nl level to form a core-shell structure with a smaller particle size, for example, a core-shell structure with a particle size of about 300 μm can be formed by dropping a liquid amount of 0.05 μ l (SGE, cone-shaped) at a minimum using a 0.1 μ l micropin. Therefore, based on the dropping device 1 provided by the invention, a core-shell structure with smaller particle size can be prepared, the requirement of the bio-printing field on the particle size can be met, the amount of the solution sucked can be accurately controlled in real time, the precision of the dropping amount at each time can be accurately controlled, the size error is effectively reduced, the requirement on the consistency of the particle size can be met, and the requirement on the difference of the particle size can also be met.
Moreover, similarly to the action surface 211, at least the portion of the inner wall of the tip 12 at the dropping end for dropping the core material liquid and/or the shell material liquid may also be set as a hydrophobic surface, that is, the entire inner wall of the tip 12 or only the inner wall of the dropping end of the tip 12 may be set as a hydrophobic surface, by this setting, sticking of the liquid to the inner wall of the tip 12 at the time of dropping can be effectively avoided, so that the titration process is easier to implement, the titration efficiency is improved, and unnecessary residue of the core material liquid and the shell material liquid in the tip 12 can also be prevented, further ensuring the sensitivity of the dropping device 1.
Furthermore, in order to facilitate the replacement and cleaning of the cleaner head 12, in the present invention, the cleaner head 12 is removably mounted to the cleaner head mounting portion, so that the cleaner head 12 can be easily removed when it is desired to replace or clean the cleaner head 12. Based on this, the core-shell structure preparation equipment of the present invention may further include a suction head storage module 3, the suction head storage module 3 is configured to store suction heads 12, and since the suction heads 12 are uniformly stored on the suction head storage module 3, centralized management of the suction heads 12 may be facilitated, and orderly picking and placing of the suction heads 12 may be ensured, especially for a case where the liquid dropping device 1 includes a plurality of suction heads 12, different storage areas may be divided on the suction head storage module 3, so as to implement storage of the suction heads 12 for storing and sucking the nuclear material liquid, the suction heads 12 for sucking the shell material liquid, and storage of the suction heads 12 for sucking the cleaning liquid or the curing agent in different areas, thereby effectively avoiding mutual confusion of the suction heads 12 with different purposes.
The liquid separating device 11 can only comprise one sucker mounting part or at least two sucker mounting parts, wherein preferably, the liquid separating device 11 comprises at least two sucker mounting parts, so that a plurality of generating units can be dripped simultaneously, a plurality of core-shell structures can be prepared simultaneously, and the preparation efficiency can be effectively improved; furthermore, the at least two suction head installation parts are arranged to be adjustable in distance, so that different interval requirements among different generation units can be met, titration efficiency is improved, and titration effect is guaranteed.
In order to facilitate the suction head 12 to suck corresponding liquid, the core-shell structure preparation apparatus of the present invention may further include a liquid storage device 6, and since the present invention at least needs to use core material liquid and shell material liquid, the liquid storage device 6 at least includes a first liquid storage space 61 and a second liquid storage space 62, where the first liquid storage space 61 is used for storing the core material liquid, and the second liquid storage space 62 is used for storing the shell material liquid, and the number of the first liquid storage space 61 and the second liquid storage space 62 may be increased or decreased according to the type and number of the core layer and the shell layer of the core-shell structure. Based on this, when needs absorb nuclear material liquid, only need control suction head 12 to remove to first stock solution space 61 department absorb can, and when needs absorb shell material liquid, then control suction head 12 to remove to second stock solution space 62 department and absorb, owing to be equipped with different stock solution spaces to different solutions, consequently can effectively avoid obscuring of different solutions for the absorption of suction head 12 is convenient and fast more. Of course, when the curing agent and/or the cleaning solution are needed in the preparation process, the liquid storage device 6 may further include a third liquid storage space and/or a fourth liquid storage space, wherein the third liquid storage space is used for storing the cleaning solution, and the fourth liquid storage space is used for storing the curing agent. The reservoir 6 of the present invention may comprise a plurality of individual containers, wherein each container becomes an individual reservoir space; alternatively, the reservoir 6 may be a unitary body having a plurality of reservoirs, such as a kit of porous materials, wherein each well is a reservoir.
In addition, the core-shell structure preparation apparatus of the present invention may further include a temperature control module, where the temperature control module is configured to control the temperature of the core material liquid and/or the shell material liquid, for example, the temperature control module may include a first temperature control module 51, where the first temperature control module 51 is configured to control the temperature of the generation unit so that the temperature of the generation unit can be consistent with the temperature required by the core material liquid and/or the shell material liquid; for another example, when the core-shell structure preparation apparatus is provided with the aforementioned liquid storage device 6, the temperature control module may include a second temperature control module 52, and the second temperature control module 52 is configured to control the temperature of the liquid storage device 6 so that the temperature of the liquid storage device 6 can be kept consistent with the temperature required by the core material liquid and/or the shell material liquid.
In order to better coat the spherical bodies with the shell material liquid and/or the shell material liquid, the core-shell structure preparation equipment provided by the invention can further comprise a material pretreatment device, wherein the material pretreatment device is used for pretreating the core material liquid and/or the shell material liquid so as to enable the core material liquid or the shell material liquid to be combined with the spherical bodies formed in the generation unit, and the shell material liquid and/or the shell material liquid can be better combined with the surfaces of the spherical bodies formed in the generation unit through pretreatment of the material pretreatment device so as to coat the spherical bodies. The combination of the core material liquid or the shell material liquid with the spherical body can be realized by charging the core material liquid or the shell material liquid with an opposite charge to the spherical body. Based on this, as an embodiment of the material pretreatment device, the material pretreatment device can be configured to be simple and easy to implement by charging the core material liquid or the shell material liquid with opposite charges to the spherical body molded in the generation unit, so that the shell material liquid and/or the shell material liquid can be attracted to the spherical body by the attraction force between the opposite charges.
In the invention, the core-shell structure preparation equipment can further comprise a displacement driving device, and the displacement driving device is used for controlling the relative motion of the dropping device 1 and the generating unit, so that the dropping device 1 can be ensured to realize accurate titration on the generating unit.
The core-shell structure preparation apparatus and the core-shell structure preparation method according to the present invention will be further described with reference to the embodiments shown in fig. 2 to fig. 4, wherein the core-shell structure preparation apparatus shown in this embodiment is a bio-brick (bioactive microsphere) preparation apparatus.
As shown in FIG. 2, in this embodiment, the apparatus for preparing bio-brick comprises a dropping device 1, a generating device, a tip storage module 3, a displacement driving device, a liquid storage device 6, a base 7 and a support frame 8 connected to the base 7.
The liquid storage device 6 is used for storing the core material liquid and the shell material liquid to be reacted and other liquids required in the preparation process, such as cleaning liquid. As shown in FIG. 2, in this embodiment, the reservoir 6 is a material reagent reservoir integrating a first reservoir 61, a second reservoir 62 and a third reservoirAnd a cartridge, wherein the first reservoir space 61 stores a core material liquid to be reacted, the second reservoir space 62 stores a shell material liquid to be reacted, and the third reservoir space stores a cleaning liquid. In order to prepare the biological brick, the core material liquid and the shell material liquid are both biocompatible liquids (such as solution and gel) with good fluidity, wherein, in the embodiment, the core material liquid is collagen solution containing cells (the number of the cells can be 1-10) 6 Secondly), the shell material liquid is polylysine and/or sodium alginate solution. The preparation steps of the polylysine solution can be as follows: polylysine (Sigma, mn150,000-300,000) was dissolved in amino acid and glucose-containing medium (DMEM high-glucose medium) at pH7.2 to give a polylysine solution with a concentration of 0.05%. The preparation steps of the sodium alginate solution can be as follows: dissolving sodium alginate in a DMEM high-sugar culture medium to obtain a sodium alginate solution with the concentration of 0.03%. Collagen solution, polylysine solution and sodium alginate solution in this embodiment are temperature sensitive solution, easily realize the control by temperature change solidification, and adopt the control by temperature change solidification can also avoid the harm of curing agent solidification mode to cell activity, consequently, this embodiment adopts the control by temperature change solidification mode to solidify nuclear layer and shell, so, need not set up the fourth stock solution space that is used for storing the curing agent in the stock solution device 6.
The dropping device 1 is used to suck up liquid and to titrate the sucked up liquid into a generating unit on the generating device with a preset particle size. As shown in fig. 2, in this embodiment, the dropping device 1 includes a liquid separating device 11 and a plurality of suction heads 12, wherein, the liquid separating device 11 includes a plurality of suction head installation parts (only one is shown in the figure) for installing the suction heads 12, the distance between the plurality of suction head installation parts can be adjusted, that is, the dropping device 1 in this embodiment is a multichannel interval-adjustable dropping device, titration on a plurality of generating units can be completed simultaneously, and different interval requirements between the generating units can be satisfied, the titration efficiency is high, in addition, the simultaneous preparation of a plurality of biological bricks with different particle sizes can be realized by setting the titration amount of each channel, biological bricks with different particle sizes can be prepared efficiently, and it is more favorable for satisfying the difference requirements on the biological bricks in practice. In this embodiment, the liquid separating device 11 further includes a compressed air filling portion, the compressed air filling portion fills compressed air into the suction head 12 mounted thereon through the suction head mounting portion, liquid in the suction head 12 is dispersed into liquid droplets with a preset particle size under the action of the compressed air and is dripped into the generating unit, and liquid separation is performed by using the compressed air, so compared with an existing vibration liquid separating mode, damage to activity of cells in the core material liquid can be significantly reduced, biological characteristic requirements of the bio-brick are met, and especially for a core-shell structure such as a bio-brick with an extremely small particle size, the advantage is more obvious.
As shown in fig. 2, in this embodiment, the dropping device 1 is an electronic dropping device, and includes a suction amount detecting portion, which can detect and display the amount of the core material liquid or the shell material liquid sucked by the suction head 12 in real time, so as to ensure that the amount of the sucked solution meets the preparation requirement, and prevent the core-shell structure preparation process from being affected due to too little or too much suction amount. In this embodiment, the amount of the liquid for the core material and/or the liquid for the shell material can be feedback-adjusted by the amount-of-suction detecting section. Therefore, the dropping device 1 of the embodiment is simpler and more convenient to operate, is beneficial to realizing the automatic preparation of the biological bricks, and obviously improves the preparation efficiency; in addition, with the dropping device 1 of this embodiment, the control of the dropping amount is easier to be realized, and the core material liquid and/or the shell material liquid can be quantitatively titrated once or many times as required, and the number and thickness of the core layer and/or the shell layer can be adjusted as required, so that the control of the particle size of the biological brick can be realized, for example, as shown in fig. 4, the core layer or the shell layer with different particle sizes can be obtained by dropping different dosages of the core material liquid and the shell material liquid into each generation unit; compared with the existing capillary tube or injector, the electronic dropping device has higher titration accuracy and smaller size error, thereby being capable of preparing the biological brick with higher size accuracy and providing a foundation for preparing the biological brick with a plurality of layers of shells with different thicknesses.
In this embodiment, the inner wall of the suction head 12 is provided with a super-hydrophobic surface to prevent the solution from adhering to the inner wall of the suction head 12, and the suction head 12 is detachably connected to the suction head mounting portion, for example, by a touch-type detachment method, so as to facilitate the replacement and cleaning of the suction head 12.
The tip storage module 3 is used to store the tips 12 detached from the tip mounting portions and the tips 12 that have not yet been used. As shown in FIG. 2, in this example, the tip storage module 3 is a tray, which is provided with a plurality of storage holes, the tips 12 are stored in the storage holes, each storage hole has a shape corresponding to the shape of the tip 12, and the plurality of storage holes are distributed on the tray in an array. In order to facilitate the use, the suction head storage module 3 is divided into a first storage area, a second storage area and a third storage area, wherein the suction heads 12 stored in the first storage area are specially used for sucking the nuclear material liquid, the suction heads 12 stored in the second storage area are specially used for sucking the shell material liquid, and the suction heads 12 stored in the third storage area are specially used for sucking the cleaning liquid, so that the mutual confusion of the suction heads 12 with different purposes can be effectively avoided.
The generating device is used for receiving the liquid dripped by the dripping device 1 and providing a reaction space for the cross-linking reaction of the core material liquid and the shell material liquid. As shown in fig. 3, in this embodiment, the generating device is an aperture plate 2, a plurality of (for example, 48, 96 or 384) blind holes 21 serving as generating units are provided on the aperture plate 2, the bottom wall of each blind hole 21 is an acting surface 211 of each blind hole 21, and in this embodiment, the acting surface 211 is a superhydrophobic surface, so that after the core material liquid and the shell material liquid are sequentially dropped into the blind holes 21, the core material liquid forms a spherical body under the action of the superhydrophobic property of the acting surface 211, and the shell material liquid is convenient to coat the periphery of the spherical body formed in the generating unit more uniformly and sufficiently, thereby ensuring that the prepared bio-brick has a better sphericity and realizing control on the forming shape of the bio-brick. Because to biological brick, the integrality of shell parcel can seriously influence the survival rate of the cell in the nuclear layer, if outside shell parcel can not be abundant or incomplete, the cell spills over from the breach or the gap of shell easily, so that the cell receives the damage easily because of can't obtain the effective protection of shell, the survival rate reduces, and this embodiment is through setting up super hydrophobic effect surface 211 for the shell can be evenly and fully cladding on the spheroid, consequently, this embodiment can effectively improve the survival rate of cell, finally improves biological brick's performance.
In order to more clearly show the effect of the superhydrophobic treatment on the action surface 211, the contrast in fig. 4 shows the molding shape of the liquid drop when the liquid drop is dropped into the bottom walls of the untreated and treated blind holes 21, as shown in fig. 4, the bottom wall of the first blind hole 21 on the left side is not superhydrophobic, and the liquid drop is flat after the liquid drop is dropped into the blind hole 21; the second from the left to the right blind holes 21 are all subjected to super-hydrophobic treatment, and liquid drops are spherical after dropping into the blind holes 21. The superhydrophobicity of the active surface 211 in this embodiment can be obtained by performing a superhydrophobic treatment on the bottom wall of the blind hole 21, or the orifice plate 21 can be made of a superhydrophobic material, so that each blind hole 21 and each part of each blind hole 21 have superhydrophobicity, and this way can also achieve the object of the present invention. The preferable mode of obtaining the superhydrophobic action surface 211 by performing superhydrophobic treatment on the bottom wall of the blind hole 21 is to dip-wash or scrub and remove dust from the orifice plate 21 in an ultraclean room with acetone, absolute ethyl alcohol, deionized water and the like, then coat a superhydrophobic coating (a coating obtained by various perfluorinated treatments or a material satisfying biocompatibility such as a nano hydrophobic layer and the like) on the inner wall of the blind hole 21 by soaking or spraying with a spray gun and the like, and then place the inner wall in a constant temperature box for heating and airing.
As can be seen from fig. 3, in this embodiment, the blind holes 21 are arranged at intervals, so that different generating units are independent from each other, which is beneficial to simultaneously preparing a plurality of core-shell mechanisms, and effectively improving the preparation efficiency, and on the other hand, the liquid drops of two adjacent blind holes 21 can be effectively prevented from converging into a large liquid drop, and the core-shell mechanisms are ensured to have a smaller particle size. Furthermore, as shown in fig. 3, the blind holes 21 are arranged in an array, that is, the blind holes 21 are uniformly distributed along the length L direction and the width B direction of the orifice plate 2 at intervals, which is more convenient for controlling the dripping device 1 to perform titration on different blind holes 21.
As shown in fig. 4, in this embodiment, the bottom wall of each blind hole 21 is U-shaped, that is, the action surface 211 is U-shaped in this embodiment, and by using the central convergence action of this U-shaped structure, the core material liquid can be more easily formed into a sphere, so that the core layer has better sphericity, and the shell material liquid can be more quickly and sufficiently coated on the sphere, thereby further improving the coating effect and increasing the coating efficiency.
In this embodiment, a liquid discharge structure (not shown in the figure) is disposed on the side wall of each blind hole 21, the liquid discharge structure includes a liquid discharge hole and a blocking member for blocking the liquid discharge hole, and the blocking member is detachably connected to the liquid discharge hole, so that the liquid discharge hole can be opened and closed as required, thereby ensuring normal preparation of the biological brick and conveniently discharging residual liquid in the blind hole 21; meanwhile, the biological brick preparation equipment further comprises an inclination control device, the inclination control device is arranged below the pore plate 2 and is used for controlling the pore plate 2 to incline towards one side of the side wall, provided with the liquid discharge hole, of the blind hole 21 when residual liquid in the blind hole 21 after the biological brick is formed needs to be discharged, so that the residual liquid in the blind hole 21 can be discharged, the liquid discharge structure arranged on the side wall of the blind hole 21 cannot influence the normal preparation of the biological brick, and particularly cannot influence the molding effect of nuclear material liquid on the bottom wall (acting surface 211) of the blind hole 21. In order to prevent erroneous discharge of the biological brick during discharge of the residual liquid, the aperture size of the drain hole may be set to be smaller than the particle size of the spherical body formed by the core liquid, and the aperture size of the drain hole may be smaller than the particle size of the biological brick if the aperture size is smaller than the particle size of the spherical body formed by the core liquid, and thus erroneous discharge of the biological brick can be avoided. The blocking piece is not necessary, and the liquid higher than the liquid discharge hole can be discharged at any time under the condition that the blocking piece is not arranged.
As shown in fig. 2, in this embodiment, the aperture plate 2 is immovably mounted on a first bottom plate 71 on the base 7 relative to the base 7, the liquid storage device 6 is immovably mounted on a second bottom plate 72 on the base 7 relative to the base 7, the tip storage module 3 is immovably mounted on the base 7 relative to the base 7, the liquid dropping device 1 is connected to the support frame 8 by a displacement driving device, the displacement driving device includes an XYZ movement module 43, the XYZ movement module 43 is mounted on the support frame 8, the liquid dropping device 1 is connected to the XYZ movement module 43, and the XYZ movement module 43 is used for driving the liquid dropping device 1 to move along the X-axis, the Y-axis and the Z-axis directions. It can be seen that, in this embodiment, the orifice plate 2, the liquid storage device 6 and the suction head storage module 3 are all fixed, and the dropping device 1 can move in three dimensions under the driving of the displacement driving device, so that the dropping device 1 can move in three directions, i.e., X-axis, Y-axis and Z-axis, relative to the orifice plate 2, the liquid storage device 6 and the suction head storage module 3, and then the dropping device 1 can accurately realize the suction of the solution and the titration of the orifice plate 2.
As can be seen from fig. 2, in this embodiment, the bio-brick preparation apparatus further includes a temperature control module. The temperature control module is used for controlling the temperature of the core material liquid and the shell material liquid. As shown in fig. 2, in this embodiment, the temperature control module includes a first temperature control module 51 and a second temperature control module 52, where the first temperature control module 51 is disposed between the first mounting plate 71 and the well plate 2, and is used to control the temperature of the generating unit, on one hand, the temperature of the generating unit can ensure the activity of cells in the core material liquid, and on the other hand, when the core layer and/or the shell layer needs to be cured, the temperature of the generating unit can be controlled by the first temperature control module 51 to reach the curing temperature of the core material liquid and/or the shell material liquid, so as to achieve temperature-controlled curing; the second temperature control module 52 is disposed between the reservoir 6 and the second bottom plate 72, and is configured to control the temperature of the reservoir 6, so that the temperature of the reservoir 6 can maintain the activity of the cells in the nuclear material liquid to be reacted. Therefore, the temperature control module in the embodiment can ensure that cells in the core material liquid maintain good activity in the preparation process, the biological brick with biological activity is finally prepared, temperature control solidification can be realized, the core layer and the shell layer are more stable, and the molding effect of the core layer and the shell layer is further ensured.
Specifically, in this embodiment, the first temperature control module 51 includes a semiconductor chilling plate as a temperature control device, a temperature controller, and a heat dissipation device, wherein the semiconductor chilling plate is used for heating or cooling the aperture plate 2 under the control of the temperature controller, and is disposed at the bottom of the aperture plate 2, the heat dissipation device is used for realizing heat transfer between the semiconductor chilling plate and the environment, and is disposed at the bottom of the semiconductor chilling plate, more specifically, the semiconductor chilling plate has a temperature control section and an non-temperature control section, the temperature control end is disposed towards the aperture plate 2, and the non-temperature control end is disposed towards the heat dissipation device; moreover, in order to ensure uniform heat transfer, in this embodiment, a heat equalizing plate 511 is further disposed between the aperture plate 2 and the semiconductor chilling plates, and the heat equalizing plate 511 can realize uniform heat transfer between the semiconductor chilling plates and the aperture plate 2. The structure of the second temperature control module 52 may be the same as or different from that of the first temperature control module 51, and in order to make the structure simpler, the structure of the second temperature control module 52 in this embodiment is the same as that of the first temperature control module 51, and details are not repeated here.
Furthermore, as can be seen from fig. 2, in this embodiment, the bio-brick preparation apparatus further includes a control device 9, and the control device 9 can control the displacement of the dripping device 1 by controlling the displacement driving device, and can also control the temperatures of the orifice plate 2 and the liquid storage device 6 to be consistent with the required temperatures of the core material liquid and the shell material liquid by controlling the first temperature control module 51 and the second temperature control module 52.
In addition, in this embodiment, the bio-brick preparation apparatus further includes a material pretreatment device (not shown in the figure) and a shaking device (not shown in the figure), wherein the material pretreatment device is connected to the liquid storage device 6, specifically to the first liquid storage space 61 and the second liquid storage space 62, and is used for making the core material liquid or the shell material liquid to carry an electric charge opposite to that of the formed spherical bodies in the generation unit, so that the core material liquid or the shell material liquid is coated on the formed spherical bodies in the generation unit, that is, in this embodiment, the core material liquid or the shell material liquid is coated on the formed spherical bodies in the generation unit in an electrostatic adsorption manner; the shaking device is arranged below the pore plate 2 and is used for applying shaking to the pore plate 2 in the process of coating the spheroids with the core material liquid or the shell material liquid so as to ensure that the core material liquid or the shell material liquid is more uniformly and fully coated on the spheroids, thereby preparing more complete and uniform biological bricks and further improving the physical and chemical properties of the biological bricks.
Based on the biological brick preparation equipment of the embodiment, the preparation method of the biological brick with the core-shell structure of the single-layer core layer and the single-layer shell layer comprises the following steps:
a pretreatment step: the core material liquid in the first liquid storage space 61 and the shell material liquid in the second liquid storage space 62 are oppositely charged by using a material pretreatment device;
a core material liquid titration step: sucking the nuclear material liquid in the first liquid storage space 61 by using the liquid dropping device 1, dispersing the sucked nuclear material liquid into liquid drops with preset particle sizes by using the liquid dropping device 1, and dropping the liquid drops into the blind hole 21 on the pore plate 2, so that the nuclear material liquid dropped into the blind hole 21 is formed into a spheroid under the action of the bottom wall (action surface 211) of the blind hole 21, and a nuclear layer is formed;
solidifying the core material liquid: the temperature of the pore plate 2 is controlled by the first temperature control module 51 until the temperature of the blind hole 21 reaches the solidification temperature of the nuclear material liquid, so that the solidification treatment of the spheroids formed in the step of titrating the nuclear material liquid is realized;
shell material liquid titration: absorbing shell material liquid in the second liquid storage space 62 by using the liquid dropping device 1, dispersing the absorbed shell material liquid into liquid drops with preset particle sizes by using the liquid dropping device 1, and dropping the liquid drops into the blind holes 21 on the pore plate 2, so that the core layer is coated by the shell material liquid dropped into the blind holes 21 under the action of the action surface 211, and in the coating process, the pore plate 21 is shaken by a shaking device to uniformly coat the core layer with the shell material liquid and perform a cross-linking reaction with the core layer to form a shell layer;
shell material liquid curing step: the temperature of the pore plate 2 is controlled by the first temperature control module 51 until the temperature of the blind hole 21 reaches the curing temperature of the shell material liquid, so that the curing treatment of the shell layer formed in the shell material liquid titration step is realized;
a residual liquid removing step: utilize dropping liquid device 1 to absorb the washing liquid in the third stock solution space and drip the washing liquid into the blind hole 21 that has remaining shell material liquid, wash the remaining shell material liquid in blind hole 21 to discharge the washing liquid outside blind hole 21 with remaining shell material liquid together.
It has been found through studies that, in order to obtain a better electrostatic adsorption effect, in the pretreatment step, the pH of the core material liquid may be adjusted, for example, the pH of the core material liquid may be adjusted to 6 to 10 (preferably to 7.6), under the pH condition, the amount of charges involved in electrostatic binding in the collagen solution containing cells is larger, and the reaction of electrostatic binding is more vigorous, so that a better electrostatic adsorption effect may be obtained; in the core material liquid curing step and the shell material liquid curing step, the temperature of the curing treatment can be controlled to be 20-40 ° (preferably 37 °), and the curing time can be set to be 5-180 minutes (the curing time can be selected within this range according to the material requirements, preferably 30 minutes).
Based on the steps, the biological brick with a single-layer core layer and a single-layer shell layer can be prepared, and in order to obtain a multi-layer core layer, the steps before the core material liquid curing step are repeated at least twice in sequence before the shell material liquid titration step, so that at least two core layers can be formed, wherein the step before the shell material liquid titration step refers to the step when the shell material liquid titration step is not carried out yet, and the steps before the core material liquid curing step refers to the steps including the core material liquid curing step; in order to obtain a multilayer shell layer, it is only necessary to repeat each step from the shell material liquid titration step to the shell material liquid solidification step at least twice after the shell material liquid solidification step, so that at least two shell layers can be formed, where "after the shell material liquid solidification step" means that the shell material liquid solidification step has been performed, and "each step from the shell material liquid titration step to the shell material liquid solidification step" means each step including the shell material liquid titration step and the shell material liquid solidification step. Therefore, the method for preparing the biological brick based on the embodiment can be used for preparing the biological brick with the single-layer core layer and the single-layer shell layer, and can also be used for preparing the biological brick with the multi-layer core layer and/or the multi-layer shell layer, so that the requirements on various core-shell structures in practice can be met. For example, the biological brick structure comprising a core layer and three shell layers can be prepared based on the biological brick preparation method, wherein the core layer is a collagen solution containing cells, the three shell layers are respectively a polylysine layer, a sodium alginate layer and a polylysine layer which are coated on the periphery of the core layer and sequentially arranged from inside to outside, the charges of the collagen solution are opposite to the charges of the polylysine layer, and the charges of the sodium alginate layer and the polylysine layer are opposite to each other, so that the mutual adsorption among the layers is ensured.
In addition, in each of the foregoing steps, the temperature control module may be used to control the temperature of the core material liquid and the shell material liquid, specifically, in the foregoing pretreatment step, the second temperature control module 52 may be used to control the temperature of the core material liquid and the shell material liquid in the liquid storage device 6, so as to ensure that the core material liquid and the shell material liquid to be reacted can maintain good biological activity; in the core material liquid titration step and the shell material liquid titration step, the second temperature control module 52 may be used to control the temperature of the core material liquid and the shell material liquid in the blind holes 21, so that the core material liquid and the shell material liquid in the blind holes 21 can maintain good biological activity.
In order to more clearly illustrate the method of using the bio-brick manufacturing apparatus of this embodiment, the following specifically describes the operation steps of the bio-brick manufacturing apparatus of this embodiment in conjunction with the above steps of the bio-brick manufacturing method.
When the step of sucking the nuclear material liquid in the step of titrating the nuclear material liquid is carried out, the operation steps of the biological brick preparation device of the embodiment are as follows: firstly, parameters such as solution suction quantity, dropping quantity, liquid separation speed and the like of the dropping device 1 are set; then, the XYZ motion module 43 drives the liquid separating device 11 to move to the position above the first storage area of the sucker storage module 3, and the suckers 12 stored in the first storage area are installed on the sucker installation part of the liquid separating device 11; and then the dropping device 1 is moved to the position above the first liquid storage space 61 of the liquid storage space 6, and the XYZ motion module 43 drives the suction head 12 to move downwards along the Z axis until the suction head extends into the first liquid storage space 61 to suck the nuclear material liquid, so that the suction of the nuclear material liquid is completed. Wherein, before the suction head 12 actually absorbs and samples the nuclear material liquid, can also rinse the suction head 12 through twice imbibition and flowing back in advance, and when formally absorbing and sampling the nuclear material liquid, can make the suction head 12 and vertical direction stretch into first stock solution space 61 with 20 contained angles, and can observe the absorption information of the nuclear material liquid that dropping liquid device 1 shows in real time, after absorbing the information and reaching preset solution absorption volume, shift out the suction head 12 from first stock solution space 61.
When the dripping step of the nuclear material liquid in the titration step of the nuclear material liquid is carried out, the operation steps of the biological brick preparation equipment of the embodiment are as follows: the dropping device 1 is moved to the upper part of the blind hole 21 of the orifice plate 21 to be titrated, so that the suction head 12 is aligned with the blind hole 21, the dropping device 1 is set to a liquid separating mode, and then the nuclear material liquid in the suction head 12 is dispersed into liquid drops with preset particle sizes to be dropped into different blind holes 21 by injecting compressed air into the suction head 12, so that the nuclear material liquid is dropped.
When the shell material liquid sucking step in the shell material liquid titration step is carried out, the operation steps of the biological brick preparation equipment of the embodiment are as follows: firstly, moving the dropping device 1 away from the upper part of the orifice plate 21, blowing liquid, and discharging residual nuclear material liquid in the suction head 12; then resetting the solution suction amount, the dropping amount and the liquid separation speed, moving the dropping device 1 to the position above the first storage area of the suction head storage module 3, detaching the suction head 12 and placing the suction head in a storage hole position of the first storage area; then the liquid separating device 11 is moved to the upper part of a second storage area of the sucker storage module 3, and the sucker 12 stored in the second storage area is arranged on the sucker installation part; and finally, the dripping device 1 is moved to the position above the second liquid storage space 62 of the liquid storage space 6, and the suction head 12 is lowered to stretch into the second liquid storage space 62 to suck shell liquid, so that the shell liquid is sucked.
When the shell material liquid dripping step in the shell material liquid titration step is performed, the operation steps of the biological brick preparation equipment of the embodiment are as follows: the dropping device 1 is moved to above the blind hole 21 titrated in the step of titrating the core material liquid of the orifice plate 21 so that the suction head 12 is aligned with the blind hole 21, the dropping device 1 is set to a liquid separating mode, and then the shell material liquid in the suction head 12 is dispersed into liquid drops with preset particle sizes by injecting compressed air into the suction head 12 and dropped into different blind holes 21, so that the shell material liquid dropping is completed.
When the residual liquid removing step is carried out, the operation steps of the biological brick preparation equipment of the embodiment are as follows: moving the liquid dropping device 1 away from the upper part of the orifice plate 21, blowing liquid, and discharging residual shell material liquid in the suction head 12; moving the liquid dropping device 1 to the position above a second storage area of the suction head storage module 3, detaching the suction head 12 and placing the suction head in a storage hole of the second storage area; then the liquid separating device 11 is moved to the upper part of the third storage area of the sucker storage module 3, and the sucker 12 stored in the third storage area is arranged on the sucker installation part; then moving the liquid dropping device 1 to the position above a third liquid storage space of the liquid storage space 6, and lowering the suction head 12 to stretch into the third liquid storage space to suck the cleaning liquid to finish the suction of the cleaning liquid; then, moving the liquid dropping device 1 to the position above the blind hole 21 titrated in the shell material liquid titration step to enable the suction head 12 to be aligned with the blind hole 21, setting the liquid dropping device 1 to be in a liquid separating mode, and dispersing the shell material liquid in the suction head 12 into liquid drops with preset particle sizes by injecting compressed air into the suction head 12 to be dropped into each blind hole 21, so as to finish the dropping of the cleaning liquid; finally, the pore plate 2 is inclined towards one side of the side wall provided with the liquid discharging structure by using the inclination control device, and the plugging piece on the liquid discharging hole is opened, so that the cleaning liquid and the residual shell material liquid are discharged out of the blind hole 21 from the liquid discharging hole.
It should be noted that, since the core material liquid curing step and the shell material liquid curing step both require a certain reaction time, the above-mentioned operation steps for performing the shell material liquid titration step and performing the residual liquid removal step can be performed by fully utilizing the reaction time without occupying additional time, and thus, the preparation method of the bio-brick according to the embodiment can significantly save the preparation time and improve the preparation efficiency.
Therefore, the core-shell structure preparation equipment of the embodiment has the following beneficial effects:
(1) The core material liquid is molded into a spheroid by utilizing the super-hydrophobicity characteristic of the action surface 211, and the shell material liquid can be more uniformly and fully coated on the core layer, so that the molding shape of the biological brick can be controlled, and the sphericity of the biological brick can be effectively improved;
(2) The action surface 211 is arranged in the blind holes 21 on the pore plate 2, compared with a pure super-hydrophobic plate with a plane configuration, the preparation efficiency can be obviously improved, the preparation processes of biological bricks in two adjacent blind holes 21 are isolated by means of the hole walls of the blind holes 21 on the pore plate 2, the independence of the preparation processes of the biological bricks can be ensured, in the preparation process of the biological bricks, shell material liquid can be more fully and uniformly wrapped by shaking the pore plate 2, the integrity and uniformity of the shell material liquid wrapping are further improved, and the physical and chemical properties of the biological bricks are further improved;
(3) The dropping device 1 adopts a compressed air liquid separating mode, so that the damage to the cell activity in the core layer of the biological brick can be effectively reduced, and the prepared biological brick can meet the requirements of the biological printing field on the biological characteristics of the biological brick;
(4) The core material liquid and the shell material liquid are respectively and accurately titrated on the action surface 211 through the electronic dropping device, so that the biological brick with smaller particle size and higher size precision can be prepared, the respective thicknesses of a core layer and a shell layer can be controlled, the sizes of the core layer and the shell layer can be independently controlled and adjusted according to needs, the repeatability is good, and the differentiation adjustment can be realized;
(5) The solidification and forming of the nuclear layer and the shell layer are realized in a temperature control mode, so that the biological activity of cells in the biological brick is kept;
(6) By means of an automatic mechanical control technology, the biological brick can be quickly prepared, the preparation time is short, the preparation efficiency is high, and the batch preparation of the biological brick is favorably realized.
As a modification of the foregoing first embodiment, the present invention also provides a second embodiment of a core-shell structure production apparatus, which is different from the foregoing first embodiment in the following points: (1) The displacement driving device also comprises an XY motion module which is arranged below the pore plate 2 and is used for driving the pore plate 2 to do two-dimensional motion in an XY plane, so that when the nuclear material liquid and the shell material liquid are dripped, the XYZ motion module 43 can be used for moving the dripping device 1 to the position above the pore plate 2, the XY motion module can be used for adjusting the position of the pore plate 2, the fine adjustment and calibration of the position of the pore plate 2 are realized, the sucker 12 and the blind hole 21 are aligned and positioned more accurately, the motion precision of the XY motion module can be 0.02mm, the preparation requirement of the biological brick can be met, and the design and processing cost is not increased too much; (2) the temperature control module no longer includes the second temperature control module 52; (3) As shown in fig. 5, the bottom wall of the blind hole 21 is plane, i.e. the active surface 211 is plane; (4) A drainage structure (not shown in the figure) is arranged on the bottom wall of the blind hole 21, and the core-shell structure preparation equipment does not comprise a tilt control device any more. Other structures of this embodiment are substantially the same as those of the first embodiment, and specific reference may be made to the description of the first embodiment, which is not repeated herein.
The above description is only exemplary of the present invention and should not be taken as limiting the invention, as any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (45)
1. The preparation method of the core-shell structure is characterized by comprising the following steps:
a core material liquid titration step: dripping core material liquid into a generating unit with an action surface (211), wherein the action surface (211) is a hydrophobic surface so that the core material liquid is singly molded into a spheroid under the action of the action surface (211) or is combined with the formed spheroid in the generating unit under the action of the action surface (211) to be further molded into a spheroid; and the combination of (a) and (b),
shell material liquid titration: and dripping shell material liquid into the generating unit to coat the shell material liquid on the formed spherical bodies in the generating unit to form a shell layer, and further forming the spherical bodies in the generating unit.
2. The core-shell structure production method according to claim 1, wherein in the shell material liquid titration step, the shell material liquid coats the spheroids molded in the generation unit on the action surface (211) to further form spheroids.
3. The method for producing a core-shell structure according to claim 1, further comprising a pretreatment step of pretreating the core material liquid and/or the shell material liquid so that the core material liquid or the shell material liquid can be bonded to the spherical bodies molded in the production unit.
4. The method for producing a core-shell structure according to claim 3, wherein in the pretreatment step, the core material liquid and/or the shell material liquid and the spherical bodies molded in the production unit are charged differently to bond the core material liquid or the shell material liquid and the spherical bodies molded in the production unit.
5. The method for producing a core-shell structure according to claim 4, further comprising a step of adjusting a pH of the core material liquid or the shell material liquid in the pretreatment step.
6. The method of manufacturing a core-shell structure according to claim 5, wherein in the step of adjusting the pH of the core material liquid, the pH of the core material liquid is adjusted to 6 to 10.
7. The method of preparing a core-shell structure according to claim 1, further comprising:
solidifying the core material liquid: setting between the core material liquid titration step and the shell material liquid titration step, and curing the spheroids formed in the core material liquid titration step;
and/or the presence of a gas in the gas,
shell material liquid curing step: and after the shell material liquid titration step, curing the shell layer formed in the shell material liquid titration step.
8. The core-shell structure preparation method according to claim 7, wherein the curing treatment includes dropping a curing agent to achieve curing or controlling a temperature to achieve curing.
9. The preparation method of the core-shell structure according to claim 8, wherein the curing treatment comprises controlling the temperature to achieve curing, wherein the temperature is controlled to be 20-40 degrees for 5-180 minutes.
10. The method of preparing a core-shell structure of claim 1, wherein the core material liquid titration step is repeated at least twice to form spheroids having at least two core layers; and/or repeating the shell material liquid titration step at least twice to form spheroids having at least two of the shell layers.
11. The method for preparing a core-shell structure according to claim 1, further comprising a shell droplet quantitative determination step: and determining the dropping amount of the shell material liquid in the shell material liquid titration step.
12. The method of preparing a core-shell structure according to claim 1, further comprising a raffinate removal step: and removing residual liquid in the generating unit after the shell material liquid titration step.
13. The method for producing a core-shell structure according to claim 12, wherein in the residual liquid removing step, a cleaning liquid is first dropped into the production cell to clean the residual shell material liquid in the production cell, and then the cleaning liquid and the residual shell material liquid are discharged to the outside of the production cell together.
14. The method for preparing a core-shell structure according to claim 1, wherein the shell material liquid titration step comprises: and shaking the generating unit in the process that the shell material liquid coats the formed spherical bodies in the generating unit to ensure that the shell material liquid uniformly coats the formed spherical bodies in the generating unit.
15. The method of preparing a core-shell structure according to claim 1, further comprising controlling the temperature of the core material liquid and the shell material liquid.
16. The core-shell structure production method according to claim 1, wherein in the core material liquid titration step, the core material liquid is dispersed into droplets of a predetermined particle diameter by using compressed air and dropped into the generation unit; and/or in the shell material liquid titration step, dispersing the shell material liquid into liquid drops with preset particle size by using compressed air, and dropping the liquid drops into the generation unit.
17. The method for preparing a core-shell structure according to any one of claims 1 to 16, wherein the hydrophobic surface is a superhydrophobic surface.
18. The utility model provides a nucleocapsid structure preparation equipment, its characterized in that includes dropping liquid device (1) and generation device, the generation device includes at least one generation unit, the generation unit has action surface (211), action surface (211) are the hydrophobic surface, dropping liquid device (1) are used for dripping into nuclear material liquid and/or shell material liquid in the generation unit, action surface (211) make nuclear material liquid shaping alone is the spheroid or makes nuclear material liquid with the spheroid that has shaped in the generation unit combines further shaping to be the spheroid, shell material liquid cladding in form the shell layer on the spheroid that has shaped in the generation unit and further form the spheroid in the generation unit.
19. Core-shell structure production apparatus according to claim 18, wherein the action surface (211) is planar or wherein the action surface (211) comprises an undercut curved surface.
20. Core-shell structure production apparatus according to claim 19, wherein the generation unit is a flat plate, and the action surface (211) is a plate surface of the flat plate; alternatively, the generating unit is an open-topped chamber, the bottom wall of the chamber is planar or comprises the concave curved surface portion, and the active surface (211) is the bottom wall of the chamber.
21. The core-shell structure manufacturing apparatus according to claim 19, wherein the concave curved surface portion is U-shaped or spherical crown-shaped.
22. The core-shell structure production apparatus according to claim 18, wherein the generating device includes at least two generating units, and at least two generating units are provided on the generating device in a spaced-apart manner from each other.
23. The core-shell structure manufacturing apparatus according to claim 18, further comprising a shaking device, wherein the shaking device is configured to enable the generation unit to generate shaking that enables the core material liquid or the shell material liquid to be uniformly coated on the formed spherical bodies in the generation unit in a process that the core material liquid or the shell material liquid coats the formed spherical bodies in the generation unit.
24. The core-shell structure manufacturing apparatus according to claim 18, wherein the generating device further includes a liquid discharge structure for discharging a liquid remaining in the generating unit after the core-shell structure is formed.
25. The core-shell structure preparation apparatus according to claim 24, wherein the generating unit is an open-topped chamber, a bottom wall of which is the action surface (211), wherein the liquid discharge structure is provided on the bottom wall of the chamber; alternatively, the drainage arrangement is provided on a side wall of the chamber.
26. The core-shell structure manufacturing apparatus according to claim 25, wherein the liquid discharge structure is provided on a side wall of the chamber, and the core-shell structure manufacturing apparatus further includes an inclination control device configured to control the generation unit to be inclined toward a side wall of the chamber where the liquid discharge structure is provided, when discharging remaining liquid in the generation unit after the core-shell structure is formed.
27. The core-shell structure fabrication apparatus of claim 24, wherein the drainage structure comprises a drainage hole in communication with the generation unit.
28. The core-shell structure manufacturing apparatus according to claim 27, wherein the liquid discharge structure further includes a blocking member that blocks the liquid discharge hole, and the blocking member is detachably connected to the liquid discharge hole.
29. The core-shell structure preparation equipment according to claim 18, wherein the liquid dropping device (1) comprises a liquid separating device (11) and at least one suction head (12), the suction head (12) can suck the core material liquid and/or the shell material liquid, the liquid separating device (11) comprises a compressed air charging portion and at least one suction head mounting portion for mounting the suction head (12), and the compressed air charging portion charges compressed air into the suction head (12) through the suction head mounting portion so as to drop the core material liquid or the shell material liquid in the suction head (12) into liquid drops with preset particle sizes.
30. The core-shell structure production apparatus according to claim 29, wherein at least a portion of an inner wall of the suction head (12) at a dropping end for dropping the core material liquid and/or the shell material liquid is a hydrophobic surface.
31. The core-shell structure production apparatus according to claim 29, wherein the dropping device (1) further includes an uptake amount detection section for detecting an uptake amount of the core material liquid or the shell material liquid that is taken up by the tip (12).
32. The core-shell structure production apparatus according to claim 29, wherein an amount of the core material liquid and/or the shell material liquid sucked is adjustable.
33. Core-shell structure production equipment according to claim 29, wherein the dripping device (1) comprises at least two suction heads (12), at least one of the at least two suction heads (12) is used for sucking the core material liquid, and at least one of the at least two suction heads (12) is used for sucking the shell material liquid.
34. The core-shell structure preparation apparatus according to claim 29, wherein the liquid separation device (11) includes at least two tip mounting portions, and a distance between the at least two tip mounting portions is adjustable.
35. The core-shell structure fabrication apparatus of claim 29, wherein the suction head (12) is detachably mounted on the suction head mounting part.
36. The core-shell structure preparation apparatus according to claim 29, further comprising a suction head storage module (3), wherein the suction head storage module (3) is used for storing the suction head (12).
37. Core-shell structure production apparatus according to claim 18, further comprising a displacement drive for controlling the relative movement of the dripping device (1) and the generating unit.
38. The core-shell structure manufacturing apparatus according to claim 18, further comprising a reservoir device (6), wherein the reservoir device (6) comprises at least a first reservoir space (61) and a second reservoir space (62), the first reservoir space (61) is used for storing the core material liquid, and the second reservoir space (62) is used for storing the shell material liquid.
39. The core-shell structure manufacturing apparatus according to claim 38, wherein the reservoir (6) further includes a third reservoir space for storing a cleaning solution; and/or the liquid storage device (6) further comprises a fourth liquid storage space, and the fourth liquid storage space is used for storing curing agents.
40. The core-shell structure preparation apparatus according to claim 18, further comprising a temperature control module for controlling a temperature of the core material liquid and/or the shell material liquid.
41. The core-shell structure preparation apparatus according to claim 40, wherein the temperature control module comprises a first temperature control module (51), and the first temperature control module (51) is used for controlling the temperature of the generation unit so that the temperature of the generation unit can be consistent with the temperature required by the core material liquid and/or the shell material liquid; and/or the core-shell structure preparation equipment further comprises a liquid storage device (6), wherein the liquid storage device (6) at least comprises a first liquid storage space (61) and a second liquid storage space (62), the first liquid storage space (61) is used for storing the core material liquid, the second liquid storage space (62) is used for storing the shell material liquid, the temperature control module comprises a second temperature control module (52), and the second temperature control module (52) is used for controlling the temperature of the liquid storage device (6) so that the temperature of the liquid storage device (6) can be consistent with the temperature required by the core material liquid and/or the shell material liquid.
42. The core-shell structure manufacturing apparatus according to claim 18, further comprising a material pretreatment device for pretreating the core material liquid and/or the shell material liquid so that the core material liquid or the shell material liquid can be combined with the formed spheroids in the generation unit.
43. The core-shell structure preparation apparatus according to claim 42, wherein the material pretreatment device is configured to charge the core material liquid and/or the shell material liquid oppositely to the formed spherical bodies in the generation unit.
44. The core-shell structure preparation apparatus of any one of claims 18 to 43, wherein the core-shell structure preparation apparatus is a bioactive microsphere preparation apparatus.
45. The core-shell structure fabrication apparatus of any of claims 18-43, wherein the hydrophobic surface is a superhydrophobic surface.
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| WO2019201270A1 (en) * | 2018-04-17 | 2019-10-24 | 四川蓝光英诺生物科技股份有限公司 | Biological cartridge, biological cartridge assembly, microsphere preparation device, shell assembling device, biobrick preparation instrument, biological ink preparation instrument, and biological ink preparation system |
| CN108530112A (en) * | 2018-06-11 | 2018-09-14 | 四川大学 | A method of preparing granular urea with super-hydrophobic face |
| CN110813395B (en) * | 2019-11-29 | 2022-02-08 | 南通大学 | Suction head droplet generating device for rapidly preparing micro droplets |
| CN111701545B (en) * | 2020-06-04 | 2022-03-25 | 上海工程技术大学 | Dripping pill production system suitable for producing microcapsule formula soil conditioner |
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| WO2006112235A1 (en) * | 2005-04-14 | 2006-10-26 | Toray Engineering Co., Ltd. | Process for producing microcapsule, microcapsule production apparatus and microcapsule sheet |
| JP2007105873A (en) * | 2006-11-13 | 2007-04-26 | Japan Science & Technology Agency | Structure having core-shell structure as component having controlled space inside, and preparation method thereof |
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| CN102843918A (en) * | 2010-03-26 | 2012-12-26 | 菲利普莫里斯生产公司 | Fabrication of core/shell capsules of different geometries and treatment thereafter |
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| WO2006112235A1 (en) * | 2005-04-14 | 2006-10-26 | Toray Engineering Co., Ltd. | Process for producing microcapsule, microcapsule production apparatus and microcapsule sheet |
| JP2007105873A (en) * | 2006-11-13 | 2007-04-26 | Japan Science & Technology Agency | Structure having core-shell structure as component having controlled space inside, and preparation method thereof |
| CN102843918A (en) * | 2010-03-26 | 2012-12-26 | 菲利普莫里斯生产公司 | Fabrication of core/shell capsules of different geometries and treatment thereafter |
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