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WO2020001341A1 - Système d'impression 3d, procédé d'impression 3d et biomatériau pour impression 3d - Google Patents

Système d'impression 3d, procédé d'impression 3d et biomatériau pour impression 3d Download PDF

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Publication number
WO2020001341A1
WO2020001341A1 PCT/CN2019/091868 CN2019091868W WO2020001341A1 WO 2020001341 A1 WO2020001341 A1 WO 2020001341A1 CN 2019091868 W CN2019091868 W CN 2019091868W WO 2020001341 A1 WO2020001341 A1 WO 2020001341A1
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WIPO (PCT)
Prior art keywords
printing
feeding
liquid
lifting platform
layer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2019/091868
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English (en)
Chinese (zh)
Inventor
欧阳宏伟
洪逸
周飞飞
章淑芳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang University ZJU
Original Assignee
Zhejiang University ZJU
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN201810699526.1A external-priority patent/CN110171127B/zh
Priority claimed from CN201810699527.6A external-priority patent/CN110171128A/zh
Priority claimed from CN201810700414.3A external-priority patent/CN110171131A/zh
Application filed by Zhejiang University ZJU filed Critical Zhejiang University ZJU
Publication of WO2020001341A1 publication Critical patent/WO2020001341A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • 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
    • 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
    • B29C64/124—Processes of additive manufacturing using only liquids or viscous materials, e.g. depositing a continuous bead of viscous material using layers of liquid which are selectively solidified
    • B29C64/129—Processes of additive manufacturing using only liquids or viscous materials, e.g. depositing a continuous bead of viscous material using layers of liquid which are selectively solidified characterised by the energy source therefor, e.g. by global irradiation combined with a mask
    • B29C64/135—Processes of additive manufacturing using only liquids or viscous materials, e.g. depositing a continuous bead of viscous material using layers of liquid which are selectively solidified characterised by the energy source therefor, e.g. by global irradiation combined with a mask the energy source being concentrated, e.g. scanning lasers or focused light sources
    • 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
    • B29C67/00—Shaping techniques not covered by groups B29C39/00 - B29C65/00, B29C70/00 or B29C73/00
    • 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
    • B33Y50/00—Data acquisition or data processing for additive manufacturing
    • B33Y50/02—Data acquisition or data processing for additive manufacturing for controlling or regulating additive manufacturing processes

Definitions

  • the invention relates to a 3D printing system, and also relates to a biological material for printing.
  • 3D printing technology is actually a rapid prototyping device using technologies such as light curing and paper lamination.
  • the design process of 3D printing is: firstly build a three-dimensional model through computer modeling software, then slice the 3D model for short, divide it into layer-by-layer sections, and then instruct the printer to print layer by layer.
  • DLP light curing printing equipment contains a liquid tank that can hold resin, which is used to hold the resin that can be cured after being irradiated with a specific wavelength of ultraviolet light.
  • the DLP imaging system is placed below the liquid tank, and its imaging surface is located at the bottom of the liquid tank.
  • a lifting mechanism for lifting the tray is arranged above the liquid tank, and the tray is stepped, thereby forming a layer of a thick molding surface between the tray (or a formed layer) and the liquid tank, and pulling up a certain height after each cross-section exposure is completed (The height is consistent with the layer thickness), so that the solidified resin that is currently cured is separated from the bottom surface of the liquid tank and bonded to the pull-up plate or the resin layer that was last molded.
  • the DLP type 3D printer has a fixed optical system, and the optical system prints only one layer at a time. Generally, the method of raising first and then lowering is used, that is, if printing with a layer thickness of 0.1mm, it is firstly raised by 5mm and then lowered by 4.9mm.
  • each molding surface is on the liquid surface. After molding, the model is immersed in the material liquid.
  • this method also has problems. The surface tension of the liquid will affect the thickness of the molding layer and the molding effect.
  • each molding surface is on the liquid surface, so the liquid tank needs to be filled each time. Even if the actual amount of material to be molded is much smaller than the volume of the liquid tank, the liquid tank must be filled to ensure each time.
  • the molding surface is on the liquid surface; and the remaining liquid cannot be used again after molding.
  • the DLP light curing printing lifting mechanism is also immersed in the liquid, and in order to make the molding surface on the liquid surface, the volume difference caused by the sinking of the lifting mechanism needs to be balanced.
  • the mechanism, balance block and tray are all located in the liquid tank. The lifting mechanism and the balance block occupy the cross-sectional area of the liquid tank, resulting in an effective molding area (tray area) smaller than the cross-sectional area of the liquid tank, and the effective molding area is small.
  • the existing artificial soft tissue preparation method of extrusion and light curing composite molding includes the following steps: 1. Model the artificial soft tissue to obtain an artificial soft tissue model; 2. Process the contour of each layer in the artificial soft tissue model: use 3D Print the layering software to calculate the contour information of each layer in the artificial soft tissue model, and use this contour information to generate the running path of the extrusion nozzle; 3. Prepare the light-curing composite solution: firstly make the living cells, growth factors and collagen solution three Mix to obtain a mixed solution, and then inject a photo-curable hydrogel into the mixed solution, and then add a visible light photoinitiator to obtain a hydrogel composite capable of maintaining a certain shape; 4.
  • the photo-curable composite solution prepared in step 3 is Raw materials, artificial soft tissue preparation using a 3D printer: 4-1, control the hydraulic extrusion head to extrude the hydrogel composite on the work platform according to the running path to form a semi-solidified colloid layer; 4-2, perform the colloid layer Light curing to obtain a cured layer.
  • the hydraulic extrusion head is fixedly connected to the light curing head. When the hydraulic extrusion head is in the working state, the light curing head is closed; when the hydraulic extrusion head is reset according to the movement track of the work, the hydraulic extrusion head is closed and the light curing head is in the Working status.
  • the disadvantages of this biological tissue molding method are: 1. No matter whether it is a DLP method or an extrusion type, multiple materials cannot be used to cooperatively complete the molding task of a biological tissue, so it is impossible to achieve mixed processing of multiple materials.
  • the active organism is a heterogeneous mixed system containing a variety of structures and various material components. The above method cannot complete the formation of a heterogeneous mixed system.
  • DLP has a fast feeding and forming speed, but wastes a lot of liquid material, and the single-use rate of the material liquid is low. This also requires an improved design of existing traditional printing, hoping to print bioactive materials with more complex structures.
  • an object of the present invention is to provide a 3D printing system capable of realizing alternate feeding of multiple materials and realizing a non-uniform mixing system.
  • a 3D printing system includes an optical system, a feeding mechanism, a lifting platform, and a cavity; the lifting platform and the cavity form a space for receiving the material from the feeding mechanism, and the lifting platform is independent of the feeding mechanism; each time the printing platform is opposed to the optical system Stepping.
  • the lifting platform steps one layer at a time.
  • the purpose of the lifting platform stepping is to enable the optical system to focus the layer to be molded and achieve light curing.
  • the feeding mechanism is outside the optical system, and the material liquid of the feeding mechanism is outside the photo-curing area of the optical system. When printing, the material liquid does not need to be shifted to perform photo-curing.
  • the independent of the lifting platform and the feeding mechanism means that the lifting platform is not integrated with the feeding mechanism, but is an independent mechanism.
  • the feeding mechanism injects the liquid material into the lifting platform in a fixed amount. The lifting of the lifting platform does not cause the supply of the feeding mechanism. material.
  • the lifting platform is a platform that can be independently lifted.
  • the lifting platform accepts the feeding of the feeding mechanism. After the lifting platform steps, it can send a signal to the feeding mechanism that it needs to feed, but the step of the lifting platform It does not directly cause the liquid to flow into the platform.
  • the lifting platform is in the light curing area of the optical system, and the material liquid in the lifting platform receives the light from the optical system to complete the light curing molding.
  • the optical system is above a lifting platform.
  • the lifting platform includes a piston
  • the piston is located in the cavity
  • the piston receives the supply
  • the piston is driven stepwise by the platform driving member.
  • the platform driver is located below the piston.
  • the upper surface of the piston is in contact with the liquid material.
  • the platform driving member is fixed to the bottom of the piston.
  • the platform driving member includes a driving motor, a screw mechanism and a slider, the screw is connected to the driving motor, the nut is fixed to the slider, and the slider is connected to the piston.
  • the screw rod mechanism converts the torque of the driving motor into linear movement, the slider steps down or up with the piston, and the cavity simultaneously serves as a guide when the piston moves.
  • the platform driving part does not occupy the contact area and space between the piston and the material liquid, and all the area of the upper surface of the piston is an effective area that can be used for light curing molding.
  • the cavity is used for containing a material liquid or a biological ink or a biological material, and the lifting platform is raised and lowered in the cavity. Each time printing is performed, the material liquid is added into the cavity. When the material liquid level in the cavity reaches the layer thickness requirement, the optical system performs light curing.
  • the printing system includes a support, and the cavity is fixed on the support.
  • the cavity is formed by a through hole provided on the block body, and the block body is fixed on the bracket.
  • the cross section of the cavity is a regular shape such as a rectangle, or a square, or a circle, or an oval.
  • the block-shaped body is provided with a channel or a slot for receiving the platform driving member. The slider of the platform driving member can be vertically translated without interference in the channel or groove of the block body.
  • the block body is a conventional shape such as a rectangular plate, a square plate, a circle, or an oval.
  • the feeding mechanism adds material to the lifting platform, and the amount of each feeding is basically equal to the amount of liquid material required to form the current layer.
  • the so-called substantially equal means that the amount of feed can meet the amount of liquid material required for molding, and the liquid level and layer thickness are in the effective curing range, not absolute equality in the mathematical sense.
  • the feeding mechanism has a feeding unit, and the feeding unit has a respective barrel, a feeding rod, a discharging nozzle, and a quantitative driving mechanism, and the feeding rod is connected to the quantitative driving mechanism.
  • the feeding rod pushes the material liquid in the material barrel to extrude from the discharging nozzle, and the discharging nozzle adds the material liquid to the lifting platform.
  • the number of the feeding units is one, or the number of the feeding units is plural. Multiple means the number of feeding units is ⁇ 2.
  • the feeding mode is controlled by the controller, which controls the feed of the quantitative drive mechanism.
  • a certain feeding unit is designated for feeding, or a plurality of feeding units alternately implement the feeding-light curing process.
  • the first feeding unit feeds and light cures, and the lifting platform steps once, and the second feeding unit feeds and light cures.
  • the lifting platform steps Once, feeding by the first feeding unit, photo-curing, ..., so, multiple feeding units alternately feed-curing. In this case, the amount of feed once per supply unit meets the amount of feed liquid required for the current layer forming.
  • the alternate feeding is a multi-unit sequential feeding, or different feeding units cross-feeding.
  • sequential feeding for example, there are a first feeding unit, a second feeding unit, and a third feeding unit, which are sequentially supplied in the order of the first, second, and third-light curing.
  • Different units cross feed, such as the first feed unit, the second feed unit and the third feed unit, the first feed unit feeds-light curing, the second feed unit feeds-light curing, and then the first One feeding unit feeds-light curing, and the third feeding unit feeds-light curing, as long as the two feedings are completed by different units.
  • a plurality of feeding units supply the materials at the same time, and then photocuring after the feeding is completed.
  • the first feeding unit and the second feeding unit feed simultaneously.
  • the total supply of all units meets the amount of liquid required for the current layer forming.
  • light curing is performed.
  • the liquid droplet dropping positions of the two units are the same or different.
  • one or more of the feeding units are fed first, and the other one or more of the feeding units are fed after the first feeding is completed, and all the feeding units are finished and then light-cured.
  • the first supply unit supplies the material first, and the second supply unit supplies the material after the first supply unit completes the supply.
  • the total amount of the supplied material meets the amount of liquid material required for the current layer forming, and the light is cured after the feeding is completed.
  • the post-feeding unit can be the same or different from the drop-feeding position of the first-feeding unit.
  • one or more molding stages are supplied with designated feeding units, one or more molding stages are fed simultaneously with multiple units, and one or several molding stages are fed with multiple units alternately.
  • the quantitative driving mechanism is used for quantitatively pushing the feeding rod, and the quantitative driving mechanism is controlled to realize the control of the feeding mode.
  • the quantitative driving mechanism includes a feeding driving member, and the feeding driving member is connected to the feeding rod.
  • the feeding driving member includes a clamp, and the feeding rod is clamped to the clamp to realize the connection between the feeding driving member and the feeding rod. When the clamp releases the feeding rod, the feeding rod is separated from the feeding driving member.
  • the feed drive uses a motor and a transmission mechanism (such as a screw mechanism), an electric push rod, and a cylinder.
  • each cartridge has its own cartridge holder, and the cartridges are fixed on the cartridge holder.
  • the barrel holder includes a fixed portion and a movable portion, the movable portion is connected to the barrel, and a locking member is provided between the movable portion and the fixed portion. After the movable part is displaced relative to the fixed part, the installation height of the barrel is raised.
  • multi-level screw holes are provided in the height direction of the movable portion
  • screw holes are provided in the fixed portion
  • the locking member is a screw or a bolt and nut.
  • Each level of screw holes corresponds to a mounting height.
  • a multi-stage screw hole is provided in the height direction of the fixing portion.
  • the position adjusting mechanism is used to adjust the position of the feeding mechanism, so that the feeding mechanism can drop the material liquid at the designated position of the lifting platform.
  • the 3D printer includes a position adjustment mechanism, and the feeding mechanism is mounted on the position adjustment mechanism.
  • Each feeding unit has an independent position adjustment mechanism. Alternatively, all the feeding units are installed in the same position adjustment mechanism. Alternatively, some feeding units are installed in the same position adjustment mechanism, and the other feeding units are installed in other position adjustment mechanisms.
  • the position adjusting mechanism includes a base, an adjusting drive member and an adjusting slider located on the base.
  • the adjusting slider has a slope, and one end of the slope near the lifting platform is low and the other end is high. The existence of the slope makes the material liquid of the barrel subject to a certain gravity, avoids the material liquid remaining in the nozzle, and maintains the accuracy of the material liquid amount during feeding.
  • the positioning slider is matched with the positioning guide, and the base is provided with a positioning limit switch. The positioning limit switch limits the displacement interval of the positioning slider.
  • Positioning drives use motors, cylinders, electric actuators, etc.
  • the cartridge holder is fixed to the positioning slider. Adjust the installation height of the barrel so that the axis of the barrel is in line with the thrust direction of the quantitative drive mechanism.
  • the printing system has a liquid discharge mechanism.
  • the gap between the piston and the cavity is matched, and the gap between the piston and the cavity is used as a drainage tank.
  • the amount of material liquid is large, and the gap between the piston and the cavity will not be discharged from the gap due to the surface tension of the material liquid.
  • the light is solidified once, the amount of the liquid becomes very small, and the uncured liquid can be drained from the drainage tank.
  • the piston and the cavity are sealed and matched, and the liquid discharge mechanism is a liquid suction pipe.
  • the pipette extends into the non-shaped area to suck away the remaining liquid.
  • the liquid suction tube is mounted on a liquid suction driving mechanism, and the liquid suction driving mechanism reciprocates to cause the liquid suction tube to enter or withdraw from the cavity.
  • the liquid suction pipe is connected to a negative pressure device. Residual liquid is sucked away by means of negative pressure.
  • the present invention provides a 3D printing method, which includes:
  • the barrel supplies material into the cavity, and the material liquid fills the space surrounded by the lifting platform and the cavity;
  • step 3 when the printing task uses only one material for printing, after step 3), repeat steps 2) -4) until the printing task is completed.
  • the feeding mechanism provides a quantity of material liquid that meets one layer of printing at a time, so that the material liquid layer is always within the light curing range of the optical system. No liquid is drained between the upper and lower layer thicknesses, or after the previous layer thickness is cured, the remaining material liquid is drained away, but the next time the material is supplied, the amount of material liquid can meet the focus of the optical layer in the optical system. How much material liquid is needed for the current printing layer, and the unsupplied material liquid is stored in the barrel, which can still be used for other printing tasks and improve the use rate of one feeding.
  • the material liquid is completely filled in the previous printing layer, and the buoyancy of the material liquid supports the cantilever or cantilever that is cured in the current layer, avoiding the collapse of the cantilever or cantilever. (Cantilever) collapsed and deformed hollow structure, the hollow structure increases the attachment area of active substances (such as cells).
  • step 4 proceed to step 5A) to determine whether the current layer needs to use another material liquid to complete the printing task. If not, the lifting platform is lowered by one layer thickness to prepare the printing of the next layer; if so, then Drain and keep the lifting platform at the current floor position.
  • the liquid discharge and lifting platform is located at the correct position, and the feeding mechanism equipped with the specified material supplies the lifting platform with the material. The system light cures the material and repeats step 5A) until the current layer is complete.
  • step 4 proceed to step 5B), determine whether the next layer is the same material as the current layer, and if not, repeat steps 2) -5); if yes, drain the liquid and keep the lifting platform at At the current floor position, a material supply mechanism equipped with a specified material supplies material to the lifting platform. After the liquid supply is completed, the optical system light-cures the material liquid.
  • the method for keeping the lifting platform at the current position includes: after printing one layer, the lifting platform does not descend; or, after printing one layer, the lifting platform descends by one layer thickness; and then resetting the lifting platform upward by one layer thickness. Draining first, then keeping the lifting platform at the current floor position, or keeping the lifting platform at the current floor position, and then draining, or keeping the lifting platform at the current floor position and draining at the same time, can be done.
  • another object of the present invention is to provide a biological material or biological ink, which can be used as a raw material for 3D printing, or a basic material that can be processed by a 3D printer, and processed by a similar printing method, and Forms a tissue or organ with a complex structure that can be used directly for a variety of purposes.
  • the purpose of the present invention is to provide a light-controlled 3D printed biological ink and its application, which can improve the problems of poor mechanical properties and slow gelation time of the existing 3D printed biological ink.
  • the invention provides a light-controlled 3D printing biological ink.
  • the glue is composed of a macromolecule modified by a light-responsive cross-linking group, a macromolecule modified by an o-nitrobenzyl-type photo-trigger, a photoinitiator, and deionized water;
  • the final mass concentration of the macromolecule modified by the photo-responsive cross-linking group and the macromolecule modified by the o-nitrobenzyl-based photo trigger is 0.1-10% by mass of deionized water, and the final mass concentration of the photoinitiator is The mass of ionized water is 0.001 to 1%;
  • the graft substitution ratio of the light-responsive crosslinking group in the macromolecule modified by the light-responsive crosslinking group is 10 to 90%, and the light-responsive crosslinking group is methacrylic acid.
  • the graft substitution rate of the o-nitrobenzyl-based light trigger in the macromolecule modified by the o-nitrobenzyl-based light trigger is 1 to 100% .
  • R 1 is -H or selected from -CO (CH 2 ) xCH 3 , -CO ( CH 2 CH 2 O) x CH 3 , -CO (CH 2 ) x (CH 2 CH 2 O) y CH 3 ester bond, selected from-(CH 2 ) x CH 3 ,-(CH 2 CH 2 O ) x CH 3 ,-(CH 2 ) x (CH 2 CH 2 O) y CH 3 , Ethers, carbonates selected from -COO (CH 2 ) x CH 3 , -COO (CH 2 CH 2 O) x CH 3 , -COO (CH 2 ) x (CH 2 CH 2 O) y CH 3 carbonate Isocyanate bonds selected from -CONH (CH 2 ) x CH 3 , -CONH (CH 2 CH 2 O) x CH 3 , -CON
  • ortho-nitrobenzyl-type photo trigger is ortho-nitrobenzyl.
  • the natural macromolecules in the macromolecules modified by the light-responsive cross-linking group and the macromolecules modified by an o-nitrobenzyl-type photo-trigger are dextran, hyaluronic acid, gelatin, sodium alginate, sulfuric acid Chondroitin, silk fibroin, chitosan, carboxymethyl cellulose or collagen, polyethylene glycol or citric acid polymer (PEGMC).
  • the photoinitiator is 2-hydroxy-4 '-(2-hydroxyethoxy) -2-methylphenylacetone (2-Hydroxy-4'-(2-hydroxyethoxy) -2-methylpropiophenone, I2959) Or one of lithium phenyl (2,4,6-trimethylbenzoyl) phosphate (lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP)); the photoinitiator is crosslinked with photoresponse
  • the mass ratio of the group-grafted macromolecules is 1 to 3: 100.
  • the graft substitution ratio of the macromolecule modified by the photo-responsive cross-linking group is 10-30%; the graft substitution ratio of the macromolecule modified by the o-nitrobenzyl type photo-trigger is 1-20%.
  • the macromolecules modified by the photo-responsive cross-linking group are methacrylic anhydride-modified gelatin having a graft substitution ratio of 10%, methacrylamide-modified gelatin having a graft substitution ratio of 90%, and graft substitution.
  • methacrylic anhydride modified gelatin 20% methacrylamide modified gelatin, 30% methacrylic anhydride modified collagen with graft substitution ratio, graft substitution ratio 90% methacrylic anhydride modified chondroitin sulfate or methacrylamide modified carboxymethylcellulose with a graft substitution rate of 10%, and acryl chloride modified polyethylene glycol with a graft substitution rate of 10%, One of glycidyl methacrylate-modified glucans with a graft substitution rate of 20%.
  • the macromolecules modified by the ortho-nitrobenzyl photo trigger are ortho-nitrobenzyl-modified hyaluronic acid with a graft substitution rate of 100% and ortho-nitrobenzyl-modification with a graft substitution rate of 50% Sodium alginate, o-nitrobenzyl modified chondroitin sulfate with a graft substitution rate of 10%, o-nitrobenzyl modified gelatin with a graft substitution rate of 30%, Nitrobenzyl-modified silk, ortho-nitrobenzyl-modified collagen with a graft substitution rate of 100% or o-nitrobenzyl-modified chitosan with a graft substitution rate of 10%, ortho-nitrobenzyl One of the benzyl-modified citric acid polymers (PEGMC).
  • PGMC benzyl-modified citric acid polymers
  • the final mass concentration of the macromolecule modified by the photo-responsive cross-linking group is 3-10% based on the mass of deionized water
  • the final mass concentration of the macromolecule modified by the o-nitrobenzyl light trigger is the mass of deionized water.
  • the total concentration is 2-4%
  • the final mass concentration of the photoinitiator is 0.03-0.2% based on the mass of deionized water.
  • the invention also provides an application of the light-controlled 3D printing ink in repairing skin damage.
  • the invention also provides an application of the light-controlled 3D printing ink in repairing articular cartilage defects.
  • the application is: printing the light-controlled 3D printing ink using a digital light processing (DLP) -based 3D printing technology to print a stent and implanting the skin defect to achieve skin tissue repair.
  • DLP digital light processing
  • the invention utilizes the principle that an o-nitrobenzyl light trigger generates an aldehyde group after being excited by light, and the generated aldehyde group and amino group can react to form a strong chemical bond.
  • the macromolecules modified by the light-responsive cross-linking group are rapidly cured under light
  • the double crosslinked network enhances mechanical properties.
  • the 3D printed porous microstructure can achieve the purpose of rapid repair of defects. It is an ideal light-controlled 3D printing ink for repairing skin defects or osteochondral defects.
  • the feeding mechanism adds materials to the area surrounded by the lifting platform and the cavity in a dropwise manner.
  • the feeding mechanism and the lifting platform are independent of each other, and no pre-feeding is needed; each added liquid and each layer are required for forming.
  • the amount of material and liquid is matched to increase the use rate of one feeding and greatly reduce the waste of material and liquid.
  • each feed is one layer at a time.
  • the uncured area remains liquid.
  • the liquid material can support the new material, thereby avoiding the collapse of the next layer of material. Precisely print the form.
  • multiple feed printing modes such as alternating printing of multiple materials layer by layer, non-uniform mixed printing of multiple materials at the same layer, and single material printing can be realized.
  • the printing mode is flexible and can realize the material
  • the heterogeneous mixed system is shaped to more realistically simulate the actual biological system.
  • the position of the liquid droplets can be controlled to more realistically simulate the actual biological system.
  • the area of the liquid surface is basically equal to the lifting platform, and the effective light curing area is large.
  • the present invention is mainly embodied in new biological materials:
  • the mechanical properties of the light-controlled 3D printing ink of the present invention can be controlled by light activation.
  • the bioglue does not contain aldehyde groups and cannot react with amino groups to form a double-layer network, so its mechanical properties are poor.
  • an aldehyde group is generated on the molecule of the o-nitrobenzyl-based light plate machine, which can quickly react with the amino group.
  • the light-controlled 3D printing ink can make the biological glue have better mechanical properties. Mechanical properties can be increased by increasing the concentration of macromolecules modified with o-nitrobenzyl light triggers.
  • the method of the invention adopts a macromolecule modified by a light-responsive cross-linking group and a macromolecule modified by an o-nitrobenzyl type photo-trigger, which has good biological safety and simple usage, and can be used in the field of tissue defect repair and regenerative medicine to achieve perfect tissue repair.
  • FIG. 1 is a model diagram (upper stent) of a cartilage print made by the present invention.
  • FIG. 2 is an overall configuration diagram of a printer of the present invention.
  • FIG. 3 is a structural diagram of a platform driving member and a lifting platform.
  • FIG. 4 is a structural diagram of a lifting platform support.
  • FIG. 5 is a schematic diagram of feeding the feeding mechanism 2 to the lifting platform 3.
  • Fig. 6 is a structural diagram of a feeding unit having a liftable cartridge holder.
  • Fig. 7 is a structural diagram of a feeding unit having a fixed-height barrel frame.
  • FIG. 8 is a configuration diagram of a position adjustment mechanism.
  • FIG. 9 is a structural diagram of a lifting platform piston.
  • FIG. 10 is a schematic diagram of a three-dimensional leather hollow structure printed using one material.
  • FIG. 11 is a schematic perspective view of the grid layer and the pillar array layer of FIG. 10 formed from the same material.
  • FIG. 12 is a schematic perspective view of the grid layer and the pillar array layer of FIG. 1 formed by using two different materials.
  • FIG. 13 is a schematic diagram of the continuous N layers in FIG. 10 being formed using one material and the remaining layers being formed using another material.
  • FIG. 14 is a physical view of a printed dermis of the model established in FIG. 10 according to the present invention.
  • FIG. 15A is a plan microstructure view of the dermis shown in FIG. 14, and FIG. 15B is a sectional view of the dermis shown in FIG. 14.
  • 16A-16C are characteristic diagrams of confocal microstructures of skin scaffolds printed using the biological ink of the present invention (cantilever structure, micron-level high-precision 3-axis communication hole, etc.).
  • Figures 17A-17C are confocal microstructure characterization diagrams of skin scaffolds printed with the biological ink of the present invention. Among them, the confocal photographs of living cell release organ cell activity characterization, the volume is 1 cubic millimeter, and cell proliferation is not affected for 7 days. Activity is greater than 95%).
  • FIG. 18 is a diagram of a cartilage model in a specific embodiment of the present invention.
  • FIG. 19 is a plan microstructure view of the printed through hole.
  • Figure 20 is a physical picture of different holes promised.
  • a 3D printing system includes an optical system 1, a feeding mechanism 2, a lifting platform 3, and a cavity 302; the lifting platform 3 and the cavity 302 form an area for receiving material from the feeding mechanism 2, and the lifting platform 3 and The feeding mechanism 2 is independent; each time the printing platform 3 is stepped relative to the optical system.
  • Fig. 1 is a skin tissue in a hollowed out state produced by a 3D printing system.
  • the lifting platform steps one layer at a time.
  • the purpose of the lifting platform stepping is to enable the optical system to focus the layer to be molded and achieve light curing.
  • the feeding mechanism is outside the optical system, and the material liquid of the feeding mechanism is outside the photo-curing area of the optical system. When printing, the material liquid does not need to be shifted to perform photo-curing.
  • the independent of the lifting platform and the feeding mechanism means that the lifting platform is not integrated with the feeding mechanism, but is an independent mechanism.
  • the feeding mechanism injects the liquid material into the lifting platform in a fixed amount. The lifting of the lifting platform does not cause the supply of the feeding mechanism. material.
  • the lifting platform is a platform that can be independently lifted.
  • the lifting platform accepts the feeding of the feeding mechanism. After the lifting platform steps, it can send a signal to the feeding mechanism that it needs to feed. However, the stepping of the lifting platform does not directly cause the material liquid to flow in. platform.
  • the lifting platform is in the light curing area of the optical system, and the material liquid in the lifting platform receives the light from the optical system to complete the light curing molding.
  • the optical system 1 is above the lifting platform 3. Every time printing, the lifting platform 3 is stepped down.
  • the lifting platform 3 includes a piston 301, which is located in the cavity 302.
  • the piston 301 receives the supply.
  • the piston 301 is driven stepwise by the platform driver 5.
  • a sealing ring 303 is provided on the piston 301.
  • the platform driver is located below the piston.
  • the upper surface of the piston is in contact with the liquid material.
  • the platform driving member 5 is fixed to the bottom of the piston 301.
  • the platform driving member 5 includes a driving motor 501, a screw mechanism 502, and a slider 503.
  • the screw mechanism 502 and the driving motor 501 The nut is fixed to the slider, and the slider 503 is connected to the piston 301.
  • the screw mechanism 502 converts the torque of the driving motor 501 into a linear movement, the slider 503 steps down or up with the piston 301, and the cavity 302 simultaneously serves as a guide when the piston 301 moves.
  • the platform driving part does not occupy the contact area and space between the piston and the material liquid, and all the area of the upper surface of the piston is an effective area that can be used for light curing molding.
  • the cavity is used for containing the material liquid, and the lifting platform is lifted in the cavity. Each time printing is performed, the material liquid is added into the cavity. When the material liquid level in the cavity reaches the layer thickness requirement, the optical system performs light curing.
  • the printing system includes a support 4, and the cavity 302 is fixed on the support 4.
  • the cavity is formed by a through hole provided on the block body, and the block body is fixed on the bracket.
  • the cross section of the cavity is a regular shape such as a rectangle, or a square, or a circle, or an oval.
  • the block-shaped body is provided with a channel or a slot for receiving the platform driving member. The slider of the platform driving member can be vertically translated without interference in the channel or groove of the block body.
  • the block body is a conventional shape such as a rectangular plate, a square plate, a circle, or an oval.
  • the feeding mechanism 2 adds material to the lifting platform 3, and the amount of each feeding is substantially equal to the amount of liquid material required to form the current layer.
  • substantially equal means that the amount of material supplied can meet the amount of liquid material required for molding, and the liquid surface may have a slight margin in the effective curing range, which is not absolute equality in the mathematical sense.
  • the feeding mechanism 2 has a feeding unit 6, and the feeding unit 6 has a respective barrel 601, a feeding rod 602, a discharging nozzle 603, and a quantitative driving mechanism 604.
  • the feeding rod 602 is connected to the quantitative driving mechanism 604.
  • the feeding rod 602 pushes the material liquid in the material cylinder 601 to be extruded from the discharging nozzle 603, and the discharging nozzle 603 drops the material liquid to the lifting platform.
  • the number of feeding units is one, or the number of feeding units is plural. Multiple means the number of feeding units is ⁇ 2.
  • the feeding mode is controlled by the controller, which controls the feed of the quantitative drive mechanism.
  • a certain feeding unit is designated for feeding, or a plurality of feeding units alternately implement the feeding-light curing process.
  • the first feeding unit feeds and light cures, and the lifting platform steps once, and the second feeding unit feeds and light cures.
  • the lifting platform steps Once, feeding by the first feeding unit, photo-curing, ..., so, multiple feeding units alternately feed-curing. In this case, the amount of feed once per supply unit meets the amount of feed liquid required for the current layer forming.
  • the alternate feeding is a multi-unit sequential feeding, or different feeding units cross-feeding.
  • sequential feeding for example, there are a first feeding unit, a second feeding unit, and a third feeding unit, which are sequentially supplied in the order of the first, second, and third-light curing.
  • Different units cross feed, such as the first feed unit, the second feed unit and the third feed unit, the first feed unit feeds-light curing, the second feed unit feeds-light curing, and then the first One feeding unit feeds-light curing, and the third feeding unit feeds-light curing, as long as the two feedings are completed by different units.
  • a plurality of feeding units supply the materials at the same time, and then photocuring after the feeding is completed.
  • the first feeding unit and the second feeding unit feed simultaneously.
  • the total supply of all units meets the amount of liquid required for the current layer forming.
  • light curing is performed.
  • the liquid droplet dropping positions of the two units are the same or different.
  • one or more of the feeding units are fed first, and the other one or more of the feeding units are fed after the first feeding is completed, and all the feeding units are finished and then light-cured.
  • the first supply unit supplies the material first, and the second supply unit supplies the material after the first supply unit completes the supply.
  • the total amount of the supplied material meets the amount of liquid material required for the current layer forming, and the light is cured after the feeding is completed.
  • the post-feeding unit can be the same or different from the drop-feeding position of the first-feeding unit.
  • one or more molding stages are supplied with designated feeding units, one or more molding stages are fed simultaneously with multiple units, and one or several molding stages are fed with multiple units alternately.
  • the quantitative driving mechanism 604 is used for quantitatively pushing the feeding rod 602 to control the quantitative driving mechanism to control the feeding mode.
  • the quantitative driving mechanism includes a feeding driving member 605, and the feeding driving member 605 is connected to the feeding rod 602.
  • the feeding driving member 605 includes a clamp 606, and the feeding rod 602 is clamped to the clamp 606 to realize the connection between the feeding driving member 605 and the feeding rod 602.
  • the clamp 606 releases the feeding lever 602
  • the feed drive uses motors and transmission mechanisms (such as screw mechanism), electric push rods, air cylinders, etc.
  • Each cartridge has its own cartridge holder, and the cartridges are fixed on the cartridge holder.
  • the cartridge holder 607 includes a fixed portion 608 and a movable portion 609.
  • the movable portion 609 is connected to the cartridge 601, and a locking member 610 is provided between the movable portion 609 and the fixed portion 608.
  • the installation height of the barrel 601 is raised.
  • multi-level screw holes are provided in the height direction of the movable portion
  • screw holes are provided in the fixed portion
  • the locking member is a screw or a bolt and nut.
  • Each level of tapped hole corresponds to a mounting height.
  • a multi-stage screw hole is provided in the height direction of the fixing portion.
  • the position adjusting mechanism is used to adjust the position of the feeding mechanism, so that the feeding mechanism can drop the material liquid at the designated position of the lifting platform.
  • the 3D printer includes a position adjustment mechanism 7, and the feeding mechanism 2 is mounted on the position adjustment mechanism 7.
  • Each feeding unit has an independent position adjustment mechanism. Alternatively, all the feeding units are installed in the same position adjustment mechanism. Alternatively, some feeding units are installed in the same position adjustment mechanism, and the other feeding units are installed in other position adjustment mechanisms.
  • the position adjusting mechanism includes a base 701, an adjusting driver 702 and an adjusting slider 703 located on the base.
  • the adjusting slider 703 has a slope, and one end of the slope near the lifting platform 3 is low and the other end is high.
  • the existence of the slope makes the material liquid of the barrel subject to a certain gravity, to avoid the material liquid remaining in the nozzle, and to maintain the precise adjustment slider of the material liquid quantity during the supply, the positioning guide is matched with the position limit switch on the base. .
  • the positioning limit switch limits the displacement interval of the positioning slider.
  • Positioning drives use motors, cylinders, electric actuators, etc.
  • the barrel holder is fixed on the positioning slider. Adjust the installation height of the barrel so that the axis of the barrel is in line with the thrust direction of the quantitative drive mechanism.
  • the two material liquids before and after can be the same material liquid or different material liquids.
  • the printing system has a liquid discharge mechanism.
  • the gap between the piston 301 and the cavity 302 is matched, and the gap between the piston 301 and the cavity 302 serves as a drainage tank.
  • the amount of material liquid is large, and the gap between the piston and the cavity will not be discharged from the gap due to the surface tension of the material liquid.
  • the light is solidified once, the amount of the liquid becomes very small, and the uncured liquid can be drained from the drainage tank.
  • the piston and the cavity are sealed and matched, and the liquid discharge mechanism is a liquid suction pipe.
  • the pipette extends into the non-shaped area to suck away the remaining liquid.
  • the liquid suction tube is mounted on a liquid suction driving mechanism, and the liquid suction driving mechanism reciprocates to cause the liquid suction tube to enter or withdraw from the cavity.
  • the liquid suction pipe is connected to a negative pressure device. Residual liquid is sucked away by means of negative pressure.
  • the present invention provides a 3D printing method, which includes:
  • the barrel supplies material into the cavity, and the material liquid fills the space surrounded by the lifting platform and the cavity;
  • the feeding mechanism provides a quantity of material liquid that meets one layer of printing at a time, so that the material liquid layer is always within the light curing range of the optical system. No liquid is drained between the upper and lower layer thicknesses, or after the previous layer thickness is cured, the remaining material liquid is drained away, but the next time the material is supplied, the amount of material liquid can meet the focus of the optical layer in the optical system. How much material liquid is needed for the current printing layer, and the unsupplied material liquid is stored in the barrel, which can still be used for other printing tasks and improve the use rate of one feeding.
  • Printing tasks include which cylinders are used for feeding, the order of feeding, the amount and location of the liquid supply, and the light curing profile of the optical system.
  • the three-dimensional hollow structure is composed of a grid layer and a column array spaced apart.
  • the printing material is loaded into a cylinder, and the cylinder feeds the cavity in a liquid state. Initially, the lifting platform is flush with the top surface of the cavity.
  • the lifting platform is lowered by a layer thickness, the barrel is fed, the optical system illuminates the liquid surface of the liquid, and the liquid is solidified according to the pattern of the light, as shown in Figures 10 and 11, a grid shape D1 with alternating skeletons and holes is formed. Layer; one layer is printed.
  • the lifting platform is lowered by one layer thickness, and the cylinder is re-supplyed to raise the liquid level to the top of the cavity; the optical system irradiates the liquid level of the liquid, and the liquid is solidified and shaped according to the pattern of light, as shown in Figures 10 and 11, D2 of the column array is formed Layer, the pillar is located at the intersection of the skeleton of the D1 layer; the cross section of the pillar is square, and the three-dimensional effect of the superposition of the D1 layer and the D2 layer is shown in FIG. 15.
  • the lifting platform is lowered by one layer thickness, and the barrel is fed again to raise the liquid level to the top of the cavity; the optical system irradiates the liquid level of the liquid, and the liquid is solidified and shaped according to the pattern of light, as shown in Figure 10, D3 is formed on the D2 layer.
  • the structure of the D1 layer and the D3 layer is the same as that of the D1 layer. From a top view, the D1 layer and the D3 layer completely overlap.
  • the material liquid fills the space between the columns of layer B. Therefore, the buoyancy of the material liquid supports the suspended part of the skeleton of layer C.
  • the material liquid buoyancy supports the cantilever beams protruding from the columns to avoid
  • the cantilever or cantilever collapse can form a three-dimensional hollow structure without the collapse and deformation of the cantilever (or cantilever).
  • the hollow structure increases the attachment area of active substances (such as cells).
  • the lifting platform is lowered by one layer thickness, and then a layer of column array is printed.
  • a three-dimensional hollow structure with a layer of grid layer and a column array layer is formed as shown in FIG. 1.
  • a method for 3D printing is applicable to two layers in each layer, including:
  • the material B is light-cured by the optical system
  • this printing method enables the same layer to be composed of two different materials.
  • the material liquid injected each time fills the space surrounded by the lifting platform and the cavity, and the material liquid is within the focusing range of the optical system.
  • the three-dimensional hollow structure is composed of a grid layer and a column array spaced apart.
  • the same layer of the hollow structure is composed of different materials (such as when printing biological organs, muscle tissue and vascular tissue are in the same layer at the same time, and the material for printing muscle tissue is different from the material for vascular tissue)
  • the two materials are respectively loaded Barrel A and barrel B (or barrel group A and barrel group B), the barrel supplies liquid into the cavity in a liquid state. Initially, the lifting platform is flush with the top surface of the cavity. Initially, the lifting platform is flush with the top surface of the cavity. Prepare to print the first layer. The lifting platform is lowered by one layer thickness.
  • the material is supplied by the cylinder A.
  • the optical system illuminates the liquid level of the liquid.
  • the liquid is solidified and shaped according to the pattern of the light.
  • Organization the main body includes orthogonal grids, the grids cross to form holes; after molding, the residual material liquid of material A is discharged; the lifting platform is lowered by one layer thickness and then reset to another layer thickness, the barrel B is fed, the optical system
  • the liquid surface of the liquid is irradiated, and the liquid is solidified and formed according to the light pattern of the first layer. As shown in FIG. 12, a wall (representing vascular tissue) around the hole is formed.
  • the printing task of the first layer is completed, and the residual material liquid of the material B is discharged.
  • the second layer is ready to be printed.
  • the lifting platform is lowered by one layer thickness, and the barrel A supplies material to form the main body (indicating muscles) of the column array.
  • the column is located at the intersection of the grid on the first layer.
  • the residual material liquid of material A is discharged; the lifting platform is lowered by one layer thickness and then reset to another layer thickness.
  • the material is supplied by the barrel B.
  • the optical system illuminates the material liquid level.
  • a wall (representing vascular tissue) is formed on the surface of each column. In a plan view, the wall of the first layer and the wall of the second layer coincide; the printing task of the second layer is completed, and the residual material liquid of the material B is discharged.
  • the molding method and lighting pattern to form the third layer are the same as the first layer; the molding method and lighting pattern to the fourth layer are the same as the second layer; ... the molding method and lighting pattern to the odd layer are the same as the first layer; The molding method and lighting pattern are the same as those of the second layer.
  • the odd-numbered layers alternate with the even-numbered layers, and each layer is printed to form a space hollow structure with a different material organization. Extending to the case where two or more materials are used for the same layer, as long as the corresponding cylinder is prepared, after each material is formed, the lifting platform is maintained at the corresponding layer position, and then the material is added, and the lighting pattern is controlled to form the image. To the structure. .
  • step 3 the order of the materials has been set in the print job, then the molding order of steps 3) -5A) is performed according to the preset order.
  • step 3 the order of various materials is not arranged in the printing task, then one material is randomly selected and printed first, until printing of all materials is completed.
  • a 3D printing method is applicable to each layer having only one material, but the entire tissue is composed of two or more materials (such as including material A, material B, and material C)
  • the method includes the following steps:
  • the barrel B supplies material to the cavity, and the material B fills the space surrounded by the lifting platform and the cavity;
  • the optical system light-cures the material B to complete the material B Curing;
  • the lifting platform drops a layer thickness in the cavity, drains the uncured material B, and reads the next layer as the current printing task;
  • the barrel C supplies material to the cavity, and the material C fills the space surrounded by the lifting platform and the cavity;
  • the optical system light-cures the material C to complete the material C Curing;
  • the lifting platform drops a layer thickness in the cavity, drains the uncured material B, and reads the next layer as the current printing task;
  • a 3D printing method is applicable to each layer having only one material, but the entire tissue is composed of two or more materials (such as including material A, material B), but, N consecutive layer thicknesses are material A; the method includes the following steps:
  • step 6 Repeat step 6) until all print tasks are completed.
  • the structure of the epidermal layer of the skin is different from that of the dermis layer, so the materials used for molding are also different.
  • the first N layers represent the dermis layer, and the same material is used for the dermis layer (for example, material A is used).
  • the subsequent layers represent the epidermal layer, and the same material is used for the epidermal layer (for example, using material B).
  • the material of the dermis layer is different from the material of the epidermis layer.
  • the first N layers are all molded using material A (whether grid layer or column array layer); after the first N layers are printed, the N + 1 layer starts, and the material B needs to be molded.
  • the remaining material liquid of material A is discharged, and then the material B is injected into the cavity, and the liquid surface reaches the top of the cavity; the N + 1 layer is formed; the subsequent layers are printed and formed with material B .
  • Teeth have enamel, dentin, and pulp.
  • the root tip of the tooth is only dentin, followed by several layers of dentin outside and pulp.
  • the method includes the following steps:
  • the current printing task (the current layer uses materials A and B) and material B is printed first, then the residual liquid of material A is drained, and the barrel B supplies the material; the optical system supplies the material B is light cured to complete the curing of material B; the lifting platform is lowered by one layer thickness in the cavity; the lifting platform is raised by one layer thickness, the residual liquid of material B is discharged, and the material is supplied by the barrel A; the optical system light-cures the material A, Complete curing of material A;
  • a method for 3D printing is suitable for each layer with multiple materials, and the tissue consists of two or more materials (such as including material A, material B, and material C). The method includes the following steps:
  • the optical system light-cures material C to complete the solidification of material C; the lifting platform drops a layer thickness in the cavity, and the residual material liquid will be discharged, and the next layer will be read as the current printing task;
  • the printing task includes materials A, B, and C. Assuming material B is printed first (including the order in the task and the randomly selected material B is printed first); barrel B supplies material to the cavity. Material B fills the space enclosed by the lifting platform and the cavity; the optical system light-cures material B to complete the curing of material B; discharges the residual material liquid, the lifting platform drops a layer thickness in the cavity, and then raises the lifting platform by a layer thickness , That is, the height when the material B is fed;
  • the cylinder C supplies the material into the cavity, and the material C fills the space surrounded by the lifting platform and the cavity; the optical system light-cures the material C to complete the curing of the material C, at this time, all materials of the current layer are printed;
  • the lifting platform drops a layer thickness in the cavity, discharges the remaining material liquid, and reads the next layer as the current printing task;
  • the barrel A supplies material into the cavity, and the material A fills the space surrounded by the lifting platform and the cavity; the optical system light-cures the material A to complete the curing of the material A, and at this time, all materials of the current layer are printed;
  • the lifting platform drops a layer thickness in the cavity, discharges the remaining material liquid, and reads the next layer as the current printing task; repeat steps 5A1) -5A3) until all materials of the current printing task are completed;
  • a high activity factor (Such as stem cells, etc.)
  • a method of 3D printing which is suitable for a layer including material A (representing muscle tissue) and material B (representing a high activity factor solution), and the material B is located at a specified position of the material A, and the material A and the material B are fused ;
  • the method includes the following steps:
  • barrel A supplies a fixed amount of material A
  • the position adjustment device adjusts barrel B to a specified position
  • barrel B supplies a fixed amount of material B
  • barrel A and barrel B together provide the current layer liquid volume
  • the optical system light-cures the current layer liquid.
  • Material B is dropped into material A to form a natural diffusion state, so that a non-uniform mixed system in which the two materials naturally diffuse can be printed.
  • the material or material liquid in the present invention refers to a material or a mixture for processing by a printer.
  • some existing biological materials can be used for printing.
  • many materials include natural polymers: collagen, silk fibers, gelatin, alginates, and synthetic polymers: polyethylene glycol (PEG) or any combination thereof can be processed in the printer of the present invention.
  • PEG polyethylene glycol
  • These materials, which are 3D printed biologically, are also called "biological inks". Although the materials themselves are traditional materials, they can all be printed using the invented printing equipment and methods.
  • This printed biological material has a three-dimensional space structure or a four-dimensional space, and can be provided with any through holes.
  • the through hole here generally refers to a planar structure or a three-dimensional structure.
  • the shape of the hole can be any shape, circle, rectangle, square, diamond, etc.
  • a three-dimensional shape is formed.
  • Each face or multiple faces of the three-dimensional shape has a hole structure, and these holes have a certain depth.
  • the holes can communicate with each other or not. Connected, or partially connected, thus forming a channel that runs through the entire three-dimensional structure or part of the three-dimensional structure.
  • Such a structure can be easily implemented by the printer of the present invention.
  • the cartridges are containers for different materials, and different cartridges can be used to hold the same material.
  • different materials or biological inks can be stored in the barrel, for example, barrel A contains one biological material, and barrel B contains another biological material.
  • the properties of the two materials are not the same.
  • the printing technology of the invention can realize the printing of complex biological tissues or organs. This is because a living organism or an organ is not uniform in structure, but has a difference in structure or biological properties.
  • mammalian skin materials have epidermis, dermis, dermis with blood vessels and tissues connected to muscles. These different parts have different structures and thicknesses, as well as excessive structures between tissues. This difference is also different. Including density, pore size, and more. In this way, if it is required to print by traditional printing, all structures or organizations are the same, and through the printing technology of the present invention, biological materials with different structures can be performed at one time.
  • the materials described in the present invention can be mixed with stem cells for processing or printing.
  • the material can be used as a scaffold structure, and the cells can be differentiated as an active cost, and finally, an active tissue can be formed.
  • the newly designed print-in of the present invention can print any suitable material.
  • the present invention provides a new 3D printed bio-ink, also called a new material.
  • the present invention provides a light-controlled 3D printed biological ink or material, the material includes a macromolecule modified by a light-responsive cross-linking group, a macromolecule modified by an o-nitrobenzyl-based light trigger, a light Initiator.
  • water is also included, such as deionized water.
  • the biomaterial of the present invention is actually a basic material. When printing is needed, it can be mixed with a solvent to form a solution state or a fluid state, and the basic material can be in a dry form. presence. Of course, it can also be directly prepared into a liquid form for storage. Optional, so as a basic material of "biological ink".
  • the final mass concentration of the macromolecules modified by the photo-responsive cross-linking group and the macromolecules modified by the o-nitrobenzyl type photo-trigger are both 0.1 to 10% by mass of deionized water.
  • the final mass concentration of the photoinitiator is 0.001 to 1% based on the mass of the deionized water.
  • the graft-replacement ratio of the photo-responsive cross-linking group in the macromolecule modified by the photo-responsive cross-linking group is 10 to 90%, and the photo-responsive cross-linking group is methacrylamide.
  • the graft substitution rate of the o-nitrobenzyl-based light trigger in the macromolecule modified by the o-nitrobenzyl-based light trigger is 1 to 100%.
  • R 1 is -H or selected from -CO (CH 2 ) xCH 3 , -CO (CH 2 CH 2 O) x CH 3 , -CO (CH 2 ) x (CH 2 CH 2 O) y CH 3 ester bond, selected from-(CH 2 ) x CH 3 , -(CH 2 CH 2 O) x CH 3 ,-(CH 2 ) x (CH 2 CH 2 O) y CH 3 , Ether bond, carbonate selected from -COO (CH 2 ) x CH 3 , -COO (CH 2 CH 2 O) x CH 3 , -COO (CH 2 ) x (CH 2 CH 2 O) y CH 3 carbonate Isocyanate bonds selected from -CONH (CH 2 ) x CH 3 , -CONH (CH 2 CH 2 O) x CH 3 ,
  • ortho-nitrobenzyl-type photo trigger is ortho-nitrobenzyl.
  • the natural biomacromolecules in the macromolecules modified by the light-responsive cross-linking group and the macromolecules modified by o-nitrobenzyl light triggers are dextran, hyaluronic acid, gelatin, One of sodium alginate, chondroitin sulfate, silk fibroin, chitosan, carboxymethyl cellulose or collagen, polyethylene glycol or citric acid polymer (PEGMC).
  • the photoinitiator is 2-hydroxy-4 '-(2-hydroxyethoxy) -2-methylphenylacetone (2-Hydroxy-4'-(2-hydroxyethoxy) -2 -methylpropiophenone (I2959) or lithium phenyl (2,4,6-trimethylbenzoyl) phosphate (lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP)); the photoinitiator
  • the mass ratio of the macromolecules grafted and modified with the light-responsive crosslinking group is 1 to 3: 100.
  • the graft substitution ratio of the macromolecule modified by the photoresponsive cross-linking group is 10-30%; the graft substitution ratio of the macromolecule modified by the o-nitrobenzyl photo trigger is 1 to 20%.
  • the macromolecules modified by the light-responsive cross-linking group are methacrylic anhydride modified gelatin with a graft substitution rate of 10%, and methacrylamide modified with a graft substitution rate of 90%.
  • the macromolecules modified by ortho-nitrobenzyl-based triggers are ortho-nitrobenzyl-modified hyaluronic acid with a graft substitution rate of 100%, and ortho-nitrobenzyl-modified hyaluronic acid with a graft substitution rate of 50%.
  • PGMC 10% o-nitrobenzyl modified citric acid polymers
  • the final mass concentration of the macromolecule modified by the photo-responsive cross-linking group is 3-10% by mass of deionized water, and the final mass concentration of the macromolecule modified by the o-nitrobenzyl photo trigger It is 2-4% based on the deionized water mass, and the final mass concentration of the photoinitiator is 0.03-0.2% based on the deionized water mass.
  • the invention also provides an application of the light-controlled 3D printing ink in repairing skin damage.
  • the invention also provides an application of the light-controlled 3D printing ink in repairing articular cartilage defects.
  • the application is: printing the light-controlled 3D printing ink using a digital light processing (DLP) -based 3D printing technology to print a stent and implanting the skin defect to achieve skin tissue repair.
  • DLP digital light processing
  • the invention utilizes the principle that an o-nitrobenzyl light trigger generates an aldehyde group after being excited by light, and the generated aldehyde group and amino group can react to form a strong chemical bond.
  • the macromolecules modified by the light-responsive cross-linking group are rapidly cured under light
  • the double crosslinked network enhances mechanical properties.
  • the 3D printed porous microstructure can achieve the purpose of rapid repair of defects. It is an ideal light-controlled 3D printing ink for repairing skin defects or osteochondral defects.
  • the materials here can exist in any form, and can be in solid form. When needed, it is configured as a liquid form for printing processing, or it is directly configured as a liquid form. When printing is required, it is directly printed.
  • materials and bio-ink are interchangeable.
  • the materials used for printing can be called materials, and they can also be called inks or bio-inks or bio-ink materials.
  • the materials or inks here can include some active ingredients, such as Including stem cells or cells or other ingredients, of course, it is only the material or ink itself that is printed or processed, and then it is also possible to add active ingredients.
  • the present invention provides specific implementation examples to illustrate the printing method of the present invention and the bio-ink material used. It can be understood that these examples are only further explanations on how to implement the present invention, and should not constitute any limitation on the present invention. The scope is based on the claims.
  • Example 1 3D printed skin for damage repair
  • FIG. 11 is a schematic diagram of a printing process using three layers as an example.
  • black indicates a bracket that needs to be printed, which is similar to a three-dimensional tetragonal structure, and the 12 sides of the bracket are printed brackets, and the bracket forms a hollow three-dimensional structure 102, forming a unit for printing brackets.
  • the unit combination forms a porous structure in the form of a cantilever beam.
  • the entire unit can form a dermal stent of any size, for example, it can be 8 mm in diameter, the thickness of the epidermis is 1 mm, and the thickness of the dermis is 1 mm, so that a skin with a thickness of 2 mm is formed.
  • the double-layer structure is designed to simulate the epidermis and dermis of the skin.
  • the epidermis is dense and the dermis is loose. Therefore, the upper structure is designed as a solid cylinder, and the lower structure is designed as a cantilever porous structure, which is suitable for cell proliferation and differentiation and blood vessels. Grow into.
  • the materials used in the stent structure are as follows: methacrylic anhydride-grafted gelatin (GelMA) and N- (2-aminoethyl) -4- (4- (hydroxymethyl) -2-methoxy -5-nitroso phenoxy-containing) butyramide (NB) grafted hyaluronic acid (HA-NB).
  • the two concentrations are: 2.5% and 0.625%, the photosensitizer concentration is 2% of the total volume, the phenol red concentration is 0.4%, and the remaining components are water.
  • Step 1 Load the material used in the support structure into the barrel. Initially, the lifting platform is flush with the top surface of the cavity;
  • Step 2 The lifting platform is lowered by one layer thickness, the barrel injects the biological material into the cavity, the liquid surface of the biological material is flush with the top surface of the cavity, and the optical system illuminates the liquid surface of the liquid material.
  • the optical pattern is a grid. Curing and forming the first layer A of the grid;
  • Step 3 The lifting platform is lowered by one layer thickness, the barrel injects the biological material into the cavity, the liquid surface of the biological material is flush with the top surface of the cavity, and the optical system illuminates the liquid surface of the liquid material.
  • the optical pattern is an array of columns. Where the grids of the layers intersect, the biological material solidifies after light exposure to form a second layer B of the pillar array;
  • Step 4 The lifting platform is lowered by one layer thickness.
  • the barrel injects the biological material into the cavity.
  • the liquid surface of the biological material is flush with the top surface of the cavity.
  • the optical system illuminates the liquid surface of the liquid material.
  • the optical pattern is the same as the first layer.
  • the third layer C of the biological material solidifies and forms the grid after the light is illuminated; during the molding of the third layer, the biological material fills the space between the columns of the second layer, so the buoyancy of the biological material supports the third layer of the grid In the suspended part of the strip, at the edges, the buoyancy of the material liquid supports the grids protruding from the column to form a cantilever beam, to avoid the collapse of the cantilever beam and the suspended portion; in the subsequent steps, the column array layer and the grid layer are alternately formed, and the shape is shown in Figure 10 The collapse-free, deformed three-dimensional hollow structure shown. All of the above printed light intensity is 50, exposure time: 1000ms.
  • FIG. 14 is a real picture of the dermis structure.
  • the microstructure looking at the microstructure, it can be seen from the top view of the dermis that it has a hollow-like structure (a structure similar to a window or a hole 101), FIG. 15A, and the solid structure 104 is a bracket forming a hole or window. 15B.
  • the light column is the support structure 101 of the printing material, and the structure of the floor space 104 is inside. It has a three-dimensional spatial structure, and the gray light columns represent the skeleton structure 104, and there is space around each light column to form a three-dimensional spatial structure.
  • the three-dimensional spatial solution structure may include stem cells or active ingredients. It is conducive to the cell's meristem, so that the printed ones are more biologically active.
  • the scaffold structure printed by this printing method has fibroblasts. After 1 week of culture, 95% of the cells still have biological activity.
  • Fig. 17A shows the fluorescence of the whole fibroblasts.
  • Fig. 17B shows the phase fluorescence of dead cells, and
  • Fig. 17C is a fitted image of living and dead cells. As can be seen from the figure, there are very few dead cells. After 15 days of cultivation, the survival rate was 90%, after 20 days of cultivation, the survival rate was 88%, and after 1 month of cultivation, the survival rate was 85%.
  • the materials printed with traditional printing technology have a very high cell death rate. After one week of culture, the general mortality rate is more than 90%, and the survival time is very short, at most 2-4 days, which cannot be used in practice.
  • the size of the dermis is determined based on the size of the repaired wound. After the dermis is printed, the dermis is covered on the wound, then a layer of epidermis is applied, and then the light is cured to repair the wound.
  • the dermis can contain fibroblasts or other active ingredients.
  • Figure 18 is a model of a cartilage stent, which includes an upper stent 901 and a lower stent 902.
  • the upper stent is 30 round holes 900
  • the side also has 30 round holes 903.
  • the holes cross the same.
  • each of the circular holes 900 above and the circular holes 903 on the side are connected, as can be seen in FIG. 1.
  • the diameter of the bracket is 4 mm
  • the thickness of the upper layer is 1 mm
  • the thickness of the lower layer is 2 mm.
  • the corresponding 30 holes in the lower layer are the same as the 30 holes in the upper layer, but there are no holes on the side next time.
  • the design is to use the scaffold for cartilage repair.
  • the top view of the lower scaffold has 30 holes.
  • the purpose is to migrate the bone marrow mesenchymal stem cells to the upper layer and help the cartilage repair.
  • the upper stent design, the middle hole is for the migration of bone marrow mesenchymal stem cells to the cartilage layer, and the side hole is for the migration of chondrocytes to the lesion, which better repairs the cartilage defect.
  • KGN small molecules can maintain the chondrocyte phenotype and promote the differentiation of bone marrow mesenchymal stem cells into chondrocytes.
  • the composition of the material used in the stent structure is as follows: the upper and lower layers are 8M methacrylic anhydride-grafted gelatin (GelMA), and the concentration is 15%.
  • the photosensitizer was 10% v / v and the phenol red concentration was 0.8%.
  • KGN small molecules were added to the upper scaffold, and the final dilution concentration was 50uM.
  • Step 1 Slicing the cartilage scaffold model by layer thickness, and the pattern of each slice is used as the light pattern of the layer.
  • the biological material is loaded into the barrel. Initially, the lifting platform is flush with the top surface of the cavity;
  • Step 2 The lifting platform is lowered by one layer thickness.
  • the barrel injects the biological material into the cavity, and the liquid surface of the biological material is flush with the top surface of the cavity.
  • the optical system illuminates the liquid surface of the liquid according to the current layer illumination pattern. The corresponding position of the hole is not covered by light, and the biological material is cured to form the first layer after the light is illuminated; repeat step 2 until the lower support is completed;
  • Step 3 When printing the lower half arc of the radial through hole of the upper bracket, repeat step 2;
  • Step 4 When printing the upper half arc of the radial through hole of the upper bracket, the next printing layer protrudes from the previous printing layer and a suspended portion appears.
  • the lifting platform is lowered by one layer thickness, and the barrel injects the biological material into the cavity.
  • the liquid surface of the biological material is flush with the top surface of the cavity; on the inner wall of the radial through hole, the uncured biological material liquid during the previous printing supports the suspended portion of the current layer to prevent the suspended portion from collapsing, thereby printing the inner wall.
  • FIG. 20 a physical mechanism diagram of the support structure printed by the printing method.
  • FIG. 19 is a microstructure diagram of each layer, and it can be seen from the top views of different cavity sizes that the side holes and the top holes are aligned with each other.
  • the fluorescence structure diagram of 400um was observed under a fluorescence microscope.

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Abstract

L'invention concerne un système d'impression 3D et un procédé d'impression 3D pouvant mettre en œuvre une alimentation alternée de multiples matériaux et mettre en œuvre un système de mélange non uniforme. Le système d'impression 3D comprend un système optique, un système d'alimentation, une plateforme de levage et d'abaissement, et une cavité. La plateforme de levage et d'abaissement et la cavité forment un espace destiné à recevoir un matériau provenant d'un mécanisme d'alimentation. La plateforme de levage et d'abaissement est indépendante du mécanisme d'alimentation. À chaque fois que l'impression est effectuée, les étapes de levage et d'abaissement de plateforme sont réalisées par rapport au système optique. Le procédé d'impression 3D comprend : 1) la préparation du système d'impression 3D et d'un liquide de matériau, et l'entrée d'une tâche d'impression ; 2) l'abaissement de la plateforme de levage et d'abaissement par une épaisseur de couche dans la cavité ; 3) l'alimentation du matériau dans la cavité par une cartouche ; et 4) la photopolymérisation du matériau liquide par le système optique. L'invention concerne également un biomatériau utilisé en tant que matière première d'impression 3D, comprenant une macromolécule modifiée par un groupe de réticulation photosensible, une macromolécule modifiée par photo-déclencheur o-nitrobenzyle, et un photo-initiateur.
PCT/CN2019/091868 2018-06-29 2019-06-19 Système d'impression 3d, procédé d'impression 3d et biomatériau pour impression 3d Ceased WO2020001341A1 (fr)

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CN201810699526.1 2018-06-29
CN201810700414.3 2018-06-29
CN201810699526.1A CN110171127B (zh) 2018-06-29 2018-06-29 一种3d打印系统
CN201810699527.6 2018-06-29
CN201810699527.6A CN110171128A (zh) 2018-06-29 2018-06-29 一种3d打印方法
CN201810700414.3A CN110171131A (zh) 2018-06-29 2018-06-29 一种用于光控3d打印的生物材料

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Publication number Priority date Publication date Assignee Title
CN103302860A (zh) * 2013-06-08 2013-09-18 王健犀 一种基于dlp投影光固化三维打印机
CN105500700A (zh) * 2014-12-30 2016-04-20 青岛智能产业技术研究院 一种彩色三维打印装置及方法
CN205767564U (zh) * 2016-07-01 2016-12-07 广州国光仪器有限公司 光敏树脂3d打印机控制装置
DE102015212069A1 (de) * 2015-06-29 2016-12-29 Siemens Aktiengesellschaft Verfahren zum Verbinden von Bauteilen und Bauteilverbindungssystem
CN106738902A (zh) * 2017-02-28 2017-05-31 深圳市金石三维打印科技有限公司 一种用于dlp 3d光固化成型的双扫描头打印装置
US20170291355A1 (en) * 2016-04-12 2017-10-12 Jing Zhang Apparatus for 3D printing
CN108187130A (zh) * 2017-09-15 2018-06-22 浙江大学 一种用于生物损伤修复或止血的试剂及其应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103302860A (zh) * 2013-06-08 2013-09-18 王健犀 一种基于dlp投影光固化三维打印机
CN105500700A (zh) * 2014-12-30 2016-04-20 青岛智能产业技术研究院 一种彩色三维打印装置及方法
DE102015212069A1 (de) * 2015-06-29 2016-12-29 Siemens Aktiengesellschaft Verfahren zum Verbinden von Bauteilen und Bauteilverbindungssystem
US20170291355A1 (en) * 2016-04-12 2017-10-12 Jing Zhang Apparatus for 3D printing
CN205767564U (zh) * 2016-07-01 2016-12-07 广州国光仪器有限公司 光敏树脂3d打印机控制装置
CN106738902A (zh) * 2017-02-28 2017-05-31 深圳市金石三维打印科技有限公司 一种用于dlp 3d光固化成型的双扫描头打印装置
CN108187130A (zh) * 2017-09-15 2018-06-22 浙江大学 一种用于生物损伤修复或止血的试剂及其应用

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