CN114683543B - High-flux biological three-dimensional printing equipment, printing method and application thereof - Google Patents
High-flux biological three-dimensional printing equipment, printing method and application thereof Download PDFInfo
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- CN114683543B CN114683543B CN202210179788.1A CN202210179788A CN114683543B CN 114683543 B CN114683543 B CN 114683543B CN 202210179788 A CN202210179788 A CN 202210179788A CN 114683543 B CN114683543 B CN 114683543B
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- 238000010146 3D printing Methods 0.000 title claims abstract description 64
- 238000007639 printing Methods 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 34
- 230000007246 mechanism Effects 0.000 claims abstract description 58
- 238000006073 displacement reaction Methods 0.000 claims abstract description 28
- 239000007921 spray Substances 0.000 claims abstract description 26
- 239000000463 material Substances 0.000 claims abstract description 11
- 238000010276 construction Methods 0.000 claims abstract description 6
- 239000007788 liquid Substances 0.000 claims description 167
- 238000003860 storage Methods 0.000 claims description 85
- 238000004132 cross linking Methods 0.000 claims description 39
- 238000002156 mixing Methods 0.000 claims description 32
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- 238000010438 heat treatment Methods 0.000 claims description 9
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- 238000012216 screening Methods 0.000 claims description 9
- 238000001514 detection method Methods 0.000 claims description 7
- 238000012546 transfer Methods 0.000 claims description 7
- 230000008859 change Effects 0.000 claims description 6
- 238000007877 drug screening Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 abstract description 11
- 210000002220 organoid Anatomy 0.000 abstract description 6
- 238000004113 cell culture Methods 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 3
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
- B29C64/20—Apparatus for additive manufacturing; Details thereof or accessories therefor
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
- B29C64/10—Processes of additive manufacturing
- B29C64/106—Processes of additive manufacturing using only liquids or viscous materials, e.g. depositing a continuous bead of viscous material
- B29C64/112—Processes of additive manufacturing using only liquids or viscous materials, e.g. depositing a continuous bead of viscous material using individual droplets, e.g. from jetting heads
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
- B29C64/30—Auxiliary operations or equipment
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
- B29C64/30—Auxiliary operations or equipment
- B29C64/307—Handling of material to be used in additive manufacturing
- B29C64/314—Preparation
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C64/00—Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
- B29C64/30—Auxiliary operations or equipment
- B29C64/307—Handling of material to be used in additive manufacturing
- B29C64/343—Metering
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B33—ADDITIVE MANUFACTURING TECHNOLOGY
- B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
- B33Y30/00—Apparatus for additive manufacturing; Details thereof or accessories therefor
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B33—ADDITIVE MANUFACTURING TECHNOLOGY
- B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
- B33Y40/00—Auxiliary operations or equipment, e.g. for material handling
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B33—ADDITIVE MANUFACTURING TECHNOLOGY
- B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
- B33Y40/00—Auxiliary operations or equipment, e.g. for material handling
- B33Y40/10—Pre-treatment
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- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Manufacturing & Machinery (AREA)
- Physics & Mathematics (AREA)
- Mechanical Engineering (AREA)
- Optics & Photonics (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
Abstract
The invention discloses a high-flux biological three-dimensional printing device, a printing method and application, wherein the printing device comprises: a control device and a displacement adjustment mechanism; the biological three-dimensional printing spray head is arranged on the displacement adjusting mechanism in a sliding manner; a three-dimensional culture chamber module having a plurality of culture chambers for containing material; under the control of the control device, the biological three-dimensional printing spray head moves to the upper part of the three-dimensional culture chamber module, and printing materials are sprayed into the corresponding culture chambers to form a structural body. The high-flux biological three-dimensional printing equipment and the method have the advantages of simple operation process, high efficiency and high construction speed, greatly reduce errors among models, and are suitable for high-flux large-scale organoid and three-dimensional cell culture.
Description
Technical Field
The invention relates to the technical field of biological manufacturing equipment, in particular to high-throughput biological three-dimensional printing equipment, a control method and application thereof.
Background
The three-dimensional biological printing is to print biological materials or cell solutions into a designed three-dimensional structure by utilizing the principle and the method of three-dimensional printing, and can construct complex structures such as controllable microspheres, three-dimensional structures containing nutrition channels, multicellular heterostructures, gradient structures with directional cell arrangement and the like.
When the three-dimensional printing equipment is used for high-throughput drug screening and detection, a cell screening model is required to be built in advance, then the high-throughput drug to be screened is added into the cell screening model to perform the action, the screening is performed according to the action result, the growth state of the cell is greatly different from the microenvironment of the cell in vivo, so that the accuracy of drug effect testing is lower, meanwhile, the high-throughput drug to be screened is added into the cell model to mainly perform operations such as liquid adding, liquid transferring and liquid changing through manpower, the process is complicated, the efficiency is lower, the time consumption is long, the labor cost is high, a large number of culture liquids with different components and different proportions are required to be configured for the high-throughput drug to be screened, the mode of configuring the various components one by one is adopted through manpower, the operation is too complicated, the volume of mixed liquid required in each experimental process is less, the total volume is generally 0.5-5mL, the accurate liquid taking amount is difficult to achieve when the liquid dispensing and liquid transferring is difficult to ensure, and the accuracy of the drug effect testing is lower.
Disclosure of Invention
To ameliorate the deficiencies of the prior art, the present invention provides a high throughput three-dimensional bioprinting apparatus comprising: a control device and a displacement adjustment mechanism; the biological three-dimensional printing spray head is arranged on the displacement adjusting mechanism in a sliding manner; a three-dimensional culture chamber module having a plurality of culture chambers for containing material; under the control of the control device, the biological three-dimensional printing spray head moves to the upper part of the three-dimensional culture chamber module, and printing materials are sprayed into the corresponding culture chambers to form a structural body.
According to the present invention, the bio three-dimensional printing head includes: biological ink box; a first temperature control device coated outside the bio-ink cartridge, the first temperature control device configured to adjust rheological properties of the internal printing solution by controlling a temperature of the bio-ink cartridge; and the micro extrusion device is provided with a micro extrusion nozzle which is arranged at the bottom of the biological ink box and used for ejecting printing solution, one end of the micro extrusion device is positioned in the biological ink box, and the printing solution is pushed in the biological ink box at a set speed through the control device, so that the printing solution is ejected from the micro extrusion nozzle at a certain flow speed. For example, the micro extrusion device is driven by a linear motor or high-pressure gas to push and pull.
Preferably, the first temperature control device is a heater, the temperature of which is adjusted to be in the range of 4 ℃ to 70 ℃, and the rheological property of the printing solution (such as the bio-ink/cell solution) in the bio-ink cartridge is adjusted by changing the temperature.
According to the invention, the three-dimensional culture chamber module comprises a culture chamber and a second temperature control device, wherein the culture chamber and the second temperature control device are arranged on a bottom plate; the second temperature control means is configured for effecting temperature control within each chamber. Such as an open heating cartridge, the bottom plate is disposed inside or outside the heating cartridge, such as the bottom plate is disposed on top of the heating cartridge.
According to the invention, the three-dimensional culture chamber module comprises 1-1000 culture chambers, for example, the three-dimensional culture chamber module comprises 1-384 chambers, for example 10-200 culture chambers.
According to the invention, the high throughput biological three-dimensional printing apparatus further comprises a liquid dispensing assembly comprising: a liquid storage mechanism which stores at least one liquid therein; the uniform mixing module comprises an oscillating device, a temperature control module and a liquid storage device, wherein the temperature control module is positioned above the oscillating device, the liquid storage device comprises a plurality of liquid storage chambers, and the oscillating device is connected or not connected with the liquid storage device and is configured to drive the solution in the liquid storage device to oscillate and uniformly mix; the temperature control module controls the temperature in the liquid storage device through the control device; and the liquid transferring device is arranged on the displacement adjusting mechanism and is configured to absorb the liquid in the liquid storage mechanism and transfer the liquid into the uniform mixing module or the culture chamber under the control of the control device.
Preferably, the oscillation means of the oscillation device includes, but is not limited to, mechanical oscillation, magnetic oscillation, ultrasonic oscillation, and stirring oscillation.
According to the invention, the liquid storage device is arranged in the heat conduction cavity, and the temperature control module is in contact with the outside or the inside of the cavity so as to heat the liquid storage device; the temperature sensor is arranged in the liquid storage device and connected with the temperature control module, the temperature sensor is configured to detect the temperature in the liquid storage device and transmit the temperature to the temperature control module, and when the temperature in the liquid storage device reaches the set temperature, the temperature control module stops heating. The reservoir has one or more reservoir chambers.
Preferably, the displacement adjusting mechanism, the biological three-dimensional printing spray head, the pipetting device, the liquid storage mechanism and the uniform mixing module are all connected with the control device, and act according to instructions sent by the control device, and the connection mode can be electric connection, including wired connection and wireless connection, for example, through wires, cables, wifi connection or Bluetooth connection.
According to the invention, the high-throughput biological three-dimensional printing equipment further comprises a photocrosslinking module and a bottom plate height measuring device, wherein the photocrosslinking module and the bottom plate height measuring device are arranged on the displacement adjusting mechanism in parallel and move along with the displacement adjusting mechanism, and the photocrosslinking module is controlled by the control device to carry out illumination on printing materials in the three-dimensional culture chamber module so as to crosslink the printing materials; the floor height measuring device is configured to measure the height of the floor on the three-dimensional culture chamber module in the Z direction under the control of the control device, and then send the height to the control device.
Preferably, the bottom plate height measuring device is provided with a mechanical firing pin measuring instrument and an infrared measuring instrument, and the mechanical firing pin measuring instrument and the infrared measuring instrument are connected with the control device.
Preferably, the printing device further comprises a sliding frame, wherein the sliding frame comprises two oppositely arranged transverse moving rods and longitudinal moving rods connected to the ends of the two transverse moving rods, and the three-dimensional movement module is slidably connected to the transverse moving rods and can move on the transverse moving rods to change the relative positions of the three-dimensional movement module and the longitudinal moving rods. For example, the three-dimensional movement module is connected to a sliding bar, for example by means of a slide.
According to the invention, the biological three-dimensional printing spray head is connected with the three-dimensional movement module through the first sliding table, the first sliding table can longitudinally move on the three-dimensional movement module, a first height adjusting sliding table is arranged between the biological three-dimensional printing spray head and the first sliding table, and the first height adjusting sliding table can vertically move on the first sliding table.
Preferably, the bottom plate height measuring device is connected with the three-dimensional motion module through a second sliding table, the second sliding table can longitudinally move on the three-dimensional motion module, a second height adjusting sliding table is arranged between the bottom plate height measuring device and the second sliding table, and the second height adjusting sliding table can drive the bottom plate height measuring device to move up and down. Preferably, the biological three-dimensional printing spray head and the bottom plate height measuring device can share a set of longitudinal movement and height adjustment sliding table.
Preferably, the photocrosslinking module is connected with the three-dimensional movement module through a third sliding table, the third sliding table can longitudinally move on the three-dimensional movement module, a third height adjustment sliding table is arranged between the photocrosslinking module and the third sliding table, the third height adjustment sliding table can drive the photocrosslinking module to move up and down, and then the distance between the photocrosslinking module and the three-dimensional culture chamber module is adjusted, so that the three-dimensional culture chamber module is accurately illuminated.
Preferably, the pipetting device is connected with the three-dimensional movement module through a fourth sliding table, and the fourth sliding table can longitudinally move on the three-dimensional movement module so as to change the relative positions of the pipetting device, the uniform mixing module, the liquid storage mechanism and the three-dimensional culture chamber module.
Preferably, the pipetting device is used in combination with a pipetting gun head comprising standard 10 μl, 100 μl, 200 μl, 1000 μl pipetting gun heads.
Preferably, the three-dimensional culture chamber module, the uniform mixing module and the liquid storage mechanism are connected to the traverse bar and can slide on the traverse bar.
As an example, a conveyor belt is arranged on the surface of the traversing rod, and the three-dimensional culture chamber module, the uniform mixing module and the liquid storage mechanism slide through the conveyor belt.
As another example, the bottom of the three-dimensional culture chamber module, the bottom of the uniform mixing module and the bottom of the liquid storage mechanism are provided with sliding blocks, the sliding rail is arranged on the transverse moving rod, and the sliding is realized through the matching of the sliding blocks and the sliding rail.
According to another aspect of the invention, there is also provided the use of any of the high-throughput biological three-dimensional printing devices described above in three-dimensional model construction, high-throughput solution configuration, drug screening and/or detection.
According to yet another aspect of the present invention, there is also provided a method of printing by any one of the above high throughput biological three-dimensional printing devices, comprising:
The control device sends a printing instruction to the biological three-dimensional printing spray head, and the biological three-dimensional printing spray head prints a culture model into a corresponding culture cavity of the three-dimensional culture cavity module.
Preferably, before the biological three-dimensional printing spray head prints the culture model into the corresponding culture cavity of the three-dimensional culture cavity module, the method further comprises the step of measuring the position of the bottom plate of the three-dimensional culture cavity module in the Z direction through the bottom plate height measuring device. Preferably, after printing the culture model, the step of cross-linking the culture model is further included.
Preferably, the crosslinking includes temperature crosslinking, ionic crosslinking, and covalent crosslinking.
As an example, in case of temperature cross-linking, the second temperature control means controls the temperature and incubation time in the culture chamber to achieve temperature cross-linking.
As another example, in the case of ionic crosslinking, an instruction is sent to the pipetting device to aspirate the crosslinking liquid and to add the corresponding culture chamber into contact with the culture model to effect the ionic crosslinking process.
As yet another example, in the case of photocrosslinking, instructions are sent to the three-dimensional culture chamber module and the photocrosslinking module, so that the three-dimensional culture chamber module is located below the photocrosslinking module, and the photocrosslinking module turns on the light source to irradiate the culture model in the culture chamber, so as to control the illumination intensity and duration, and realize the photocrosslinking process.
According to still another aspect of the present invention, there is also provided a method for high-throughput drug screening and detection by any one of the above high-throughput biological three-dimensional printing apparatuses, comprising the steps of:
S1, constructing a cell/tissue screening model by adopting the printing method;
s2, absorbing corresponding stock solution from the stock solution device by utilizing the liquid transfer device, and adding the stock solution into the uniform mixing module for mixing to obtain a drug solution to be screened;
s3, adding the drug solution to be screened in the step S2 into the cell/tissue screening model of the step S1 for culture, and obtaining screening and detection results.
Preferably, the step S2 includes: the control device controls the liquid-moving device to absorb the stock solution in the corresponding liquid storage tank according to the preset component proportion, and the stock solution is moved to the upper part of the uniform mixing module and injected into the corresponding liquid storage cavity for oscillation mixing. Preferably, the suction speed of the stock solution from the liquid storage tank is that the stock solution is sucked up from the first to the second.
Preferably, step S3 includes: and controlling the pipetting device to suck the drug solution to be screened in the corresponding liquid storage chamber, moving the pipetting device to the position above the corresponding culture chamber in the three-dimensional culture chamber module, and injecting the drug solution to be screened into the corresponding culture chamber. Preferably, the sucking speed from the liquid storage chamber of the uniform mixing module is fast and then slow.
The beneficial effects of the invention are that
1) The high-throughput biological three-dimensional printing equipment provided by the invention can realize automatic biological three-dimensional printing, can realize the stacking and forming of materials sprayed out of the nozzles on a three-dimensional space by moving the micro-extrusion nozzles on a three-dimensional moving platform and combining with a bottom plate height measuring device, and can further construct a complex three-dimensional structure, and further construct a tissue/organ model, such as a controllable microsphere, a three-dimensional structure containing a nutrition channel, a multicellular heterostructure, a gradient structure with directional arrangement of cells and other complex structures. Compared with the traditional manual construction method, the automatic printing mode greatly reduces errors among models, has higher construction speed, has the advantage of high-throughput large-scale construction, and can print organoid/three-dimensional cell culture models in an orifice plate with 1-384 chambers.
2) The high-throughput biological three-dimensional printing equipment can measure the positions of the bottom plates of the three-dimensional culture chamber module one by one according to the bottom plate height measuring device, and further accurately print the organoid/three-dimensional cell culture model in the chamber.
3) The automatic liquid preparation mechanism can realize liquid adding, liquid transferring and liquid changing fully automatically, can transfer liquid and take liquid in the three-dimensional direction, greatly reduces operation errors, can customize an operation flow as required, has strong expansibility and wide application prospect, can be suitable for various operation scenes, and can realize fully automatic planning for multi-step operation. In addition, the automatic liquid preparation mechanism is also provided with vibration mixing and temperature control, so that the mixing is more sufficient, the treatment requirements of various samples are met, the experimental result is more accurate, the preparation of mixed liquid with various different component ratios can be simultaneously carried out, and the high-flux use requirement is met.
4) The high-throughput biological three-dimensional printing equipment and method provided by the invention have the advantages of simple operation process, high efficiency and high speed, and are suitable for high-throughput large-scale organoid and three-dimensional cell culture.
Drawings
Fig. 1 is a schematic structural diagram of a high throughput biological three-dimensional printing device and an automated liquid dispensing mechanism according to an embodiment of the present invention.
Fig. 2 is a schematic diagram of electrical control signal connection of a high throughput biological three-dimensional printing device according to an embodiment of the present invention.
FIG. 3 is a schematic flow chart of high throughput biological three-dimensional printing according to an embodiment of the present invention.
Fig. 4 is a schematic diagram of electrical signal connection of a high-throughput automated liquid dispensing mechanism according to an embodiment of the present invention.
The device comprises a 1-control device, a 2-displacement adjusting mechanism, a 21-traversing rod, a 22-pipetting height adjusting sliding table, a 23-third height adjusting sliding table, a 24-first height adjusting sliding table, a 3-biological three-dimensional printing spray head, a 31-first sliding table, a 32-biological ink box, a 33-first temperature control device, a 34-micro extrusion nozzle, a 35-micro extrusion device, a 4-three-dimensional culture chamber module, a 41-second temperature control device, a 5-bottom plate height measuring device, a 51-second sliding table, a 52-mechanical firing pin measuring instrument, a 53-second height adjusting sliding table, a 6-photocrosslinking module, a 61-third sliding table, a 7-pipetting device, a 71-pipetting liquid executing mechanism, a 72-fourth sliding table, an 8-liquid storage mechanism, a 9-uniform mixing module, a 91-oscillating device and a 92-temperature control module, and a 93-liquid storage device.
Detailed Description
The apparatus, method and use of the present invention will be described in further detail below with reference to specific examples. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
Referring to fig. 1-4 comprehensively, the invention provides a high-throughput biological three-dimensional printing device, which comprises a sliding frame, a control device 1, a displacement adjusting mechanism 2, a biological three-dimensional printing spray head 3, a three-dimensional culture chamber module 4, a bottom plate height measuring device 5, a photo-crosslinking module 6, a pipetting device 7, a uniform mixing module 9 and a plurality of liquid storage mechanisms 8. The displacement adjusting mechanism 2, the biological three-dimensional printing spray head 3, the three-dimensional culture chamber module 4, the bottom plate height measuring device 5, the photo-crosslinking module 6 and the uniform mixing module 9 are all connected with the control device 1, for example, electrically connected, and the position and the action of the control device 1 are controlled. As shown in fig. 1, the sliding frame comprises a longitudinal moving rod and two oppositely arranged transverse moving rods, the longitudinal moving rods are connected to the ends of the two transverse moving rods, the displacement adjusting mechanism 2 is arranged on the transverse moving rods and connected with the transverse moving rods through sliding blocks, and the displacement adjusting mechanism 2 can reciprocate on the transverse moving rods to change the relative positions with the longitudinal moving rods. The biological three-dimensional printing spray head 3, the bottom plate height measuring device 5, the photo-crosslinking module 6 and the pipetting device 7 are all arranged on the displacement adjusting mechanism 2 and can move under the drive of the displacement adjusting mechanism 2.
The biological three-dimensional printing spray head 3 is connected with the displacement adjusting mechanism 2 through a first sliding table 31, the first sliding table 31 can longitudinally move on the displacement adjusting mechanism 2, a first height adjusting sliding table 24 is arranged between the biological three-dimensional printing spray head 3 and the first sliding table 31, the first height adjusting sliding table 24 can move up and down on the first sliding table 31, and further, the biological three-dimensional printing spray head 3 can be adjusted in the transverse, longitudinal and up-down three-dimensional directions, and matching with any position in the three-dimensional culture cavity module 4 is achieved. The biological three-dimensional printing spray head 3 stores printing solution, so that the printing solution can be sprayed and printed into the three-dimensional culture chamber module 4 to form a structural body.
In this embodiment, the bio-three-dimensional printing head 3 includes a bio-ink cartridge 32, a temperature control device 33, a micro-extrusion nozzle 34, and a micro-extrusion device 35, the micro-extrusion nozzle 34 being disposed at the bottom of the bio-ink cartridge 32 for ejecting a printing solution. One end of the micro-extrusion device 35 is connected with the control device 1, the other end is positioned in the biological ink box 32, and under the action of a signal output by the control device 1, the printing solution is pushed in the biological ink box 32 at a set speed, so that the printing solution is ejected from the micro-extrusion nozzle 34 at a certain flow speed. Preferably, the micro-extrusion device 35 is driven by a linear motor or high-pressure gas to push and pull.
As shown in fig. 1, the first temperature control device 33 is wrapped outside the bio-ink cartridge 32 for controlling the temperature of the bio-ink cartridge 32. For example, the temperature control device 33 may be a heater with a temperature in the range of 4-70 ℃ to adjust the rheological properties of the printing solution (e.g., bio-ink/cell solution) within the bio-ink cartridge 32 by changing the temperature.
According to the invention, the three-dimensional culture chamber module 4 comprises several culture chambers and the second temperature control means 41, preferably the three-dimensional culture chamber module 4 comprises 1-1000 culture chambers, for example 1-384 culture chambers. The culture chambers are positioned on a bottom plate arranged above the sliding frame, and each bottom plate is provided with 1 or more culture chambers; for example, 1-10 culture chambers are provided on each bottom plate. The second temperature control means 41 may be one or more for effecting temperature control in each culture chamber. The culture chamber may be an open heating cartridge with a bottom plate disposed inside or outside the heating cartridge, such as at the top of the heating cartridge.
The liquid storage mechanism 8 comprises a plurality of independent liquid storage tanks, and the liquids stored in different liquid storage tanks can be the same or different, and are configured and stored according to actual needs. Preferably, a cover may be provided on the liquid storage mechanism 8.
As shown in fig. 1, the uniform mixing module 9 includes an oscillating device 91, a temperature control module 92 and a liquid storage device 93, where the oscillating device 91 is disposed at the bottom of the liquid storage device 93 and is used to drive the liquid storage device 93 to vibrate, so that the solution in the liquid storage device 93 is uniform. The oscillation means 91 may oscillate by mechanical oscillation, magnetic oscillation, ultrasonic oscillation or stirring oscillation. The temperature control module 92 is in contact with the liquid storage device 93 for controlling the temperature in the liquid storage device 93, for example, the liquid storage device 93 is disposed in a heat conducting chamber, the temperature control module 92 is in contact with the outside or the inside of the chamber, and the temperature control module 92 can generate heat and transfer heat into the chamber to heat the liquid storage device 93. The temperature sensor may be further disposed in the liquid storage device 93, and the temperature sensor is connected to the temperature control module 92, and is configured to detect the temperature in the liquid storage device 93 and transmit the detected temperature to the temperature control module 92, and when the temperature in the liquid storage device 93 reaches the set temperature, the temperature control module 92 stops heating. Preferably, the reservoir 93 has 1-96 or more reservoir chambers.
The bottom plate height measuring device 5 is used for measuring the Z-direction height of the bottom plate on the three-dimensional culture chamber module 4, the mechanical firing pin measuring instrument 52 and the infrared measuring instrument are arranged on the bottom plate height measuring device 5, and the mechanical firing pin measuring instrument 52 and the infrared measuring instrument are used for measuring and comparing simultaneously to perform more accurate positioning.
As shown in fig. 1, the bottom plate height measuring device 5 is connected with the displacement adjusting mechanism 2 through the second sliding table 51, the second sliding table 51 can longitudinally move on the displacement adjusting mechanism 2, a second height adjusting sliding table 53 is arranged between the bottom plate height measuring device 5 and the second sliding table 51, the second height adjusting sliding table 53 can drive the bottom plate height measuring device 5 to move up and down, and further, adjustment of the bottom plate height measuring device 5 in the transverse, longitudinal and up-down three-dimensional directions is achieved, matching with any position in the three-dimensional culture chamber module 4 is achieved, and height measurement is conducted on any position of the three-dimensional culture chamber module 4.
In another embodiment of the present invention, the biological three-dimensional printing nozzle 3 and the bottom plate height measuring device 5 may share a set of vertical movement and height adjustment sliding tables, for example, the first sliding table 31 and the second sliding table 51 are integrated (referred to as an integrated horizontal sliding table), the first height adjustment sliding table 24 and the second height adjustment sliding table 53 are integrated (referred to as an integrated height sliding table), and the biological three-dimensional printing nozzle 3 and the bottom plate height measuring device 5 are connected to the integrated horizontal sliding table through the integrated height sliding table and then connected to the displacement adjustment mechanism 2.
The photo-crosslinking module 6 is connected with the displacement adjusting mechanism 2 through a third sliding table 61, the third sliding table 61 can longitudinally move on the displacement adjusting mechanism 2, a third height adjusting sliding table 23 is arranged between the photo-crosslinking module 6 and the third sliding table 61, the third height adjusting sliding table 23 can drive the photo-crosslinking module 6 to move up and down, and then the distance between the photo-crosslinking module 6 and the three-dimensional culture chamber module 4 is adjusted, illumination is accurately carried out on the three-dimensional culture chamber module 4, and a good crosslinking effect is achieved.
The pipetting device 7 comprises a pipetting liquid executing mechanism 71, a fourth sliding table 72 and a pipetting liquid height adjusting sliding table 22, wherein the pipetting liquid executing mechanism 71 is connected with the pipetting liquid height adjusting sliding table 22 through the fourth sliding table 72, the pipetting liquid executing mechanism 71 is used for realizing liquid transfer by sucking liquid and splashing liquid, the pipetting liquid executing mechanism 72 and the pipetting liquid height adjusting sliding table 22 are connected with the displacement adjusting mechanism 2, the fourth sliding table 72 can longitudinally move on the pipetting liquid height adjusting sliding table 22 so as to change the relative positions between the pipetting device 7 and the uniform mixing module 9, the liquid storage mechanism 8 and the three-dimensional culture chamber module 4, and liquid taking and pipetting operations are realized well.
The three-dimensional culture chamber module 4, the uniform mixing module 9 and the liquid storage mechanism 8 are arranged on the transverse rod and can slide on the transverse rod, for example, a conveying belt is arranged on the surface of the transverse rod, and the three-dimensional culture chamber module 4, the uniform mixing module 9 and the liquid storage mechanism 8 slide through the conveying belt; or the bottoms of the three-dimensional culture cavity module 4, the uniform mixing module 9 and the liquid storage mechanism 8 are provided with sliding blocks, the transverse moving rod is provided with sliding rails matched with the sliding blocks, and the sliding is realized through the matching of the sliding blocks and the sliding rails.
Referring to fig. 3, the invention further provides a control method of the high-throughput biological three-dimensional printer, which comprises the following steps:
s1: the control device 1 controls the three-dimensional culture chamber module to move to a printing position below the nozzle of the biological three-dimensional printer.
S2: the bottom plate height measuring device measures the positions of the three-dimensional culture chamber module in the Z direction of the bottom plate one by one; and transmitting and storing the measurement data in a control module of the control device 1, synthesizing a printing instruction by the control module according to the bottom plate height information and the pre-stored model parameters, and sending the printing instruction to the biological three-dimensional printing nozzle.
S3: after receiving the instruction, the biological three-dimensional printing spray head prints organoid/three-dimensional cell culture models one by one in the corresponding three-dimensional culture chamber according to the instruction; the models printed in the different incubation chambers may be the same or different.
S4: the control device sends a moving instruction and a crosslinking instruction (comprising crosslinking temperature, illumination intensity, illumination distance, illumination time, whether crosslinking liquid needs to be added or not, and the like), the three-dimensional culture chamber module moves to the lower part of the photocrosslinking module, and the organoids in the three-dimensional culture chamber module and the three-dimensional cell model are subjected to crosslinking operation under illumination to obtain the structural body.
Crosslinking in the present invention includes temperature crosslinking, ionic crosslinking and covalent crosslinking, but is not limited thereto, and the crosslinking conditions of different crosslinking modes are different.
In the case of temperature crosslinking, an instruction is given to the second temperature control device 41 to precisely control the temperature and the incubation time in the culture chamber, thereby realizing a precise temperature crosslinking process.
And when the ionic crosslinking is performed, sending a command to the pipetting device to suck the crosslinking liquid and adding the crosslinking liquid into a corresponding culture chamber to realize an accurate ionic crosslinking process.
When the three-dimensional culture chamber module is in photocrosslinking, an instruction is sent to the three-dimensional culture chamber module and the photocrosslinking module, so that the three-dimensional culture chamber module is positioned below the photocrosslinking module, the photocrosslinking module adjusts the distance between the three-dimensional culture chamber module and the control module according to the parameter information sent by the control module, and the light source is turned on to control the illumination intensity and the duration time, so that an accurate photocrosslinking process is realized.
The invention also provides a high-flux automatic liquid preparation method, which comprises the following steps:
step S1: and regulating and controlling the temperature of the liquid storage device according to a preset experimental design.
Step S2: sucking stock solution from a plurality of liquid storage tanks of the liquid storage mechanism 8 into a liquid storage device 93 of the uniform mixing module according to a preset component proportion; wherein one or more reservoirs may be used to store any of a variety of stock solutions.
Step S3: and carrying out oscillation and uniform mixing operation on the mixed liquid in the liquid storage device according to the preset experimental design parameters.
Step S4: the mixed liquid in the liquid storage device 93 is sucked up and transferred to the corresponding culture chamber, and acts with the structure body to perform drug screening.
The ratio of the raw liquid components obtained in each liquid storage cavity in the liquid storage device can be different or the same, and in the sucking process, the volumes of the raw liquids of different components sucked away can be controlled by selecting the size of a liquid-transferring gun head of the liquid-transferring device and the setting of the liquid-transferring volume of the liquid-transferring device, and the accurate control of the liquid-taking amount of the sucked mixed liquid can be realized by the method.
Preferably, before the stock solution is sucked, each liquid storage tank is marked and the component information is stored in a control module of the control device 1; and after the stock solutions with different components are sucked into the stock solution chambers, each stock solution chamber is marked, and component information is stored in the control module, so that errors in automatic pipetting are prevented.
The raw liquid is sucked from the liquid storage tank at a high sucking speed and then at a low sucking speed, when the raw liquid starts to be sucked, the raw liquid is sucked at a high sucking speed so as to improve the efficiency, when the suction amount of the stock solution approaches to the volume designed in advance, the suction speed is reduced to prevent excessive suction of the stock solution, thereby realizing accurate control of the liquid taking. And according to the reserves of the liquid storage tanks recorded in the control module, calculating the volume of the residual stock solution and storing the calculated volume in the control module, and stopping the liquid taking operation when the volume of the stock solution stored in the liquid storage tank is close to a preset critical value, and adding the stock solution into the liquid storage tank.
When the liquid storage cavity of the uniform mixing module is used for sucking mixed liquid, the sucking speed is fast and then slow, and when the mixed liquid starts to be sucked, the mixed liquid is sucked at a fast sucking speed to improve the efficiency, and when the sucking amount of the mixed liquid is close to the volume designed in advance, the sucking speed is reduced to prevent the excessive sucking of the mixed liquid, so that the accurate control of liquid taking is realized. And according to the reserves of each liquid storage chamber recorded in the control module, calculating the volume of the residual mixed liquid and storing the volume in the control module, stopping liquid taking operation when the volume of the mixed liquid in the liquid storage chamber is close to a preset critical value, and sucking the stock solution from the liquid storage tank to the liquid storage chamber according to the preset component proportion, and oscillating and uniformly mixing. The liquid can be sucked in a three-dimensional direction by moving the suction.
In order to meet the requirement of high flux, more liquid storage tanks and liquid storage chambers are required to be arranged, so that the distribution ranges of the liquid storage tanks and the liquid storage chambers are wider, and liquid can be conveniently sucked from the liquid storage tanks and the liquid storage chambers with wider distribution ranges by moving in three dimension directions in the sucking process. When absorbing the stoste in the liquid storage groove, can use same liquid rifle head component to absorb, also can use a plurality of liquid rifle head components to absorb simultaneously, but when absorbing to the stoste of different compositions, need to change and get liquid rifle head original paper, avoid causing the pollution to influence the accuracy nature of experiment. The replacement of the original liquid-taking gun head is fully automatic. In order to avoid pollution of the stock solution or the mixed solution, save the use amount of the liquid taking gun head element and shorten the liquid taking time, the stock solution or the mixed solution with the same component is sucked, and the stock solution or the mixed solution with the same component is sucked again after the suction of the stock solution or the mixed solution with the same component is completed.
Compared with the prior art, the automatic liquid preparation mechanism can realize liquid adding, liquid transferring and liquid changing in a full-automatic mode, can perform liquid transferring and liquid taking in a three-dimensional direction, greatly reduces operation errors, can customize an operation flow as required, is high in expansibility, has wide application prospect, can be suitable for various operation scenes, and can realize full-automatic planning for multi-step operation. The mechanism can simultaneously carry out the configuration of mixed liquid with various component ratios, and meets the requirement of high-flux use.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (12)
1. A high throughput biological three-dimensional printing device, comprising:
A control device (1) and a displacement adjustment mechanism (2);
The biological three-dimensional printing spray head (3) is arranged on the displacement adjusting mechanism (2) in a sliding manner;
a three-dimensional culture chamber module (4) having a plurality of culture chambers for containing material;
Under the control of the control device (1), the biological three-dimensional printing spray head (3) moves to the upper part of the three-dimensional culture chamber module (4), and printing materials are sprayed into the corresponding culture chambers to form a structural body;
The biological three-dimensional printing spray head (3) is connected with the three-dimensional movement module through a first sliding table (31), the first sliding table (31) can longitudinally move on the three-dimensional movement module, a first height adjusting sliding table (24) is arranged between the biological three-dimensional printing spray head (3) and the first sliding table (31), and the first height adjusting sliding table (24) can move up and down on the first sliding table (31);
the high-throughput biological three-dimensional printing device further comprises a liquid dispensing assembly, the liquid dispensing assembly comprising:
A liquid storage mechanism (8) in which at least one liquid is stored;
the uniform mixing module (9) comprises an oscillating device (91), a temperature control module (92) positioned above the oscillating device (91) and a liquid storage device (93) comprising a plurality of liquid storage chambers, wherein the oscillating device (91) is connected or disconnected with the liquid storage device (93) and is configured to drive a solution in the liquid storage device (93) to oscillate and uniformly mix; the temperature control module (92) controls the temperature in the liquid storage device (93) through the control device (1);
A pipetting device (7) arranged on the displacement adjustment mechanism (2) and configured to aspirate the liquid in the liquid storage mechanism (8) and transfer the liquid into the homogeneous mixing module (9) or the culture chamber under the control of the control device (1);
The three-dimensional culture chamber module (4) comprises a culture chamber and a second temperature control device (41) which are positioned on a bottom plate, wherein one or more of the culture chamber and the second temperature control device (41) are arranged; the second temperature control means (41) is configured for effecting temperature control within each chamber;
the printing equipment also comprises a photocrosslinking module (6) and a bottom plate height measuring device (5), wherein the photocrosslinking module (6) is arranged on the displacement adjusting mechanism in parallel and moves along with the displacement adjusting mechanism, and the photocrosslinking module is used for carrying out illumination on printing materials in the three-dimensional culture chamber module (4) under the control of the control device (1) so as to crosslink the printing materials;
the bottom plate height measuring device (5) is configured to measure the height of the bottom plate on the three-dimensional culture chamber module (4) in the Z direction under the control of the control device (1) and then send the height to the control device (1);
The bottom plate height measuring device (5) is connected with the three-dimensional movement module through a second sliding table (51), the second sliding table (51) can longitudinally move on the three-dimensional movement module, a second height adjusting sliding table is arranged between the bottom plate height measuring device (5) and the second sliding table (51), and the second height adjusting sliding table can drive the bottom plate height measuring device (5) to move up and down.
2. The high throughput biological three-dimensional printing apparatus of claim 1, wherein the biological three-dimensional printing head (3) comprises:
a biological cartridge (32);
a first temperature control device (33) wrapped outside the bio-ink cartridge (32), the first temperature control device (33) configured to adjust rheological properties of the internal printing solution by controlling a temperature of the bio-ink cartridge (32); and
And the micro extrusion device (35) is provided with a micro extrusion nozzle (34) arranged at the bottom of the biological ink box (32) and used for ejecting printing solution, one end of the micro extrusion device (35) is positioned inside the biological ink box (32), and the printing solution is pushed in the biological ink box at a set speed through the control device (1) so that the printing solution is ejected from the micro extrusion nozzle (34) at a certain flow speed.
3. The high throughput biological three-dimensional printing apparatus of claim 1, wherein said reservoir (93) is disposed within a thermally conductive chamber, said temperature control module (92) being in contact with the outside or inside of the chamber to heat the reservoir (93);
the temperature sensor is arranged in the liquid storage device and connected with the temperature control module (92), the temperature sensor is configured to detect the temperature in the liquid storage device (93) and transmit the temperature to the temperature control module (92), and when the temperature in the liquid storage device (93) reaches the set temperature, the temperature control module (92) stops heating.
4. A high throughput biological three-dimensional printing apparatus according to any one of claims 1 to 3, further comprising a carriage comprising two oppositely disposed traversing bars and a longitudinal bar connected to the ends of the traversing bars, the three-dimensional movement module being slidably connected to the traversing bars and being movable on the traversing bars to vary the relative position with the longitudinal bar.
5. The high-throughput biological three-dimensional printing device according to claim 1, wherein the photo-crosslinking module (6) is connected with the three-dimensional movement module through a third sliding table (61), the third sliding table (61) can longitudinally move on the three-dimensional movement module, a third height adjusting sliding table (23) is arranged between the photo-crosslinking module (6) and the third sliding table (61), the third height adjusting sliding table (23) can drive the photo-crosslinking module (6) to move up and down, and further the distance between the photo-crosslinking module (6) and the three-dimensional culture chamber module (4) is adjusted, so that the three-dimensional culture chamber module (4) is accurately illuminated.
6. The high-throughput biological three-dimensional printing device according to claim 1, wherein the pipetting device (7) is connected with the three-dimensional motion module through a fourth sliding table (72), and the fourth sliding table (72) can longitudinally move on the three-dimensional motion module to change the relative positions between the pipetting device (7) and the uniform mixing module (9), the liquid storage mechanism (8) and the three-dimensional culture chamber module (4).
7. Use of the high throughput biological three-dimensional printing device of any one of claims 1 to 6 in three-dimensional model construction, high throughput solution configuration, drug screening and/or detection.
8. A method of printing using the high throughput biological three-dimensional printing device of any one of claims 1 to 6, comprising: the control device (1) sends a printing instruction to the biological three-dimensional printing spray head (3), and the biological three-dimensional printing spray head (3) prints a culture model into a culture cavity corresponding to the three-dimensional culture cavity module (4).
9. The method of printing by a high throughput biological three-dimensional printing apparatus according to claim 8, wherein the biological three-dimensional printing head (3) further comprises the step of measuring the Z-direction position of the floor of the three-dimensional culture chamber module (4) by the floor height measuring device (5) before printing the culture model into the corresponding culture chamber of the three-dimensional culture chamber module (4);
and after printing the culture model, the method further comprises the step of crosslinking the culture model.
10. A method of high throughput drug screening and detection using the high throughput biological three-dimensional printing apparatus of any one of claims 1-6, comprising the steps of:
S1, constructing a cell/tissue screening model by adopting the method of claim 8 or 9;
s2, sucking corresponding stock solution from a liquid storage device (93) by using a liquid transfer device, and adding the stock solution into a uniform mixing module (9) for mixing to obtain a drug solution to be screened;
s3, adding the drug solution to be screened in the step S2 into the cell/tissue screening model of the step S1 for culture, and obtaining screening and detection results.
11. The method according to claim 10, wherein the step S2 comprises: the control device (1) controls the liquid-moving device to absorb the stock solution in the corresponding liquid storage tank according to the preset component proportion, and moves the stock solution to the upper part of the uniform mixing module, and fills the stock solution into the corresponding liquid storage cavity for oscillation mixing.
12. The method according to claim 10, wherein step S3 comprises: and controlling the pipetting device to suck the drug solution to be screened in the corresponding liquid storage chamber, moving the pipetting device to the position above the corresponding culture chamber in the three-dimensional culture chamber module, and injecting the drug solution to be screened into the corresponding culture chamber.
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| CN205255520U (en) * | 2015-06-10 | 2016-05-25 | 中国科学技术大学 | Three -dimensional printing device of imitative body of biological tissue optics |
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| CN110643479A (en) * | 2018-06-26 | 2020-01-03 | 深圳市北科生物科技有限公司 | Liquid distribution station |
| CN110561747B (en) * | 2019-08-22 | 2021-12-03 | 浙江大学 | Desktop-level biological 3D printing system |
| CN111607514A (en) * | 2020-05-28 | 2020-09-01 | 杭州电子科技大学 | Biological 3D print platform is mixed to compound biomaterial developments |
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| CN113172876A (en) * | 2021-05-20 | 2021-07-27 | 上海曼恒数字技术股份有限公司 | Biological printing system and method for accurately positioning cells |
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| CN104873300A (en) * | 2015-05-11 | 2015-09-02 | 浙江大学 | Apparatus for printing three dimensional biological structure having built-in nutrition channels |
| CN107418872A (en) * | 2016-08-31 | 2017-12-01 | 四川蓝光英诺生物科技股份有限公司 | Prepare the device of microballoon and prepare the method for microballoon |
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