CN107523136A - The degradable 3D printing bio-ink of temperature-responsive and 3D printing method - Google Patents
The degradable 3D printing bio-ink of temperature-responsive and 3D printing method Download PDFInfo
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- CN107523136A CN107523136A CN201710790405.3A CN201710790405A CN107523136A CN 107523136 A CN107523136 A CN 107523136A CN 201710790405 A CN201710790405 A CN 201710790405A CN 107523136 A CN107523136 A CN 107523136A
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
- C09D11/00—Inks
- C09D11/30—Inkjet printing inks
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- 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
- B33Y10/00—Processes of additive manufacturing
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- 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
- B33Y70/00—Materials specially adapted for additive manufacturing
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
- C09D11/00—Inks
- C09D11/30—Inkjet printing inks
- C09D11/38—Inkjet printing inks characterised by non-macromolecular additives other than solvents, pigments or dyes
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Abstract
A kind of degradable 3D printing bio-ink of temperature-responsive and 3D printing method, the 3D printing bio-ink is made up of temperature-responsive hydrogel and biological cell, the hydrogel is made up with other additives mixeds according to a certain percentage of the PLGA PEG PLGA triblock copolymers with temperature-responsive, because the critical inversion temperature scope of the PLGA PEG PLGA triblock copolymers of temperature-responsive is 20 33 DEG C, with being solidified into gel characteristic in 37 DEG C of body temperature, so that the 3D printing bio-ink of the present invention possesses same temperature-responsive and degradable characteristic.Temperature-responsive and degradable characteristic of the present invention using above-mentioned 3D printing bio-ink, the bio-ink of pre-agglomeration is prepared before the printing, to the abjection moisture that is rapidly heated after the slow freezing of model after printing, the porous structural model containing biological cell can be formed, the nutrition and metabolism passage of loose structure can be obtained, is advantageous to obtain bigger thicker institutional framework by 3D printing.
Description
Technical field
The present invention relates to biological technical field, especially 3D biometric prints technical field, more particularly to a kind of temperature-responsive
Property degradable 3D printing bio-ink and 3D printing method.
Background technology
3D printing can be rapidly and efficiently the product for producing personalization, thus be gradually introduced in biologic medical industry,
To be used for tissue and organ transplant by 3D printing technique.《The current research of biological 3D printing and application》(powder metallurgy work
Industry, the 4th phase of volume 25, in August, 2015, Zhang Hongbao etc.) in application to 3D biometric print technologies be divided into different levels progress
Introduce, it is incorporated herein by reference.The basic skills of the 3D biometric prints of higher level is, by seeded with living celis to biofacies
In biodegradable support hold and last, then cultivated in bioreactor so that cell relies on support to be formed
Spatial growth generation needed for organize.For example, the A of CN 106085949 disclose a kind of reconstruction urethra based on 3D printing shaping
The method of prosthese；Epithelioid cell, class smooth muscle cell are divided into by cell inducible factors, is then converted into cell drop,
The cell drop has cell and nutrient solution hydrogel to mix, and the bio-ink for being available for medical 3D printer to use is made；Choosing
Select the support ink of hydrogel that collagen mixes with alginates as timbering material；Cell or cell aggregation are controlled by computer
Body, the eject position and dynamics of ratio and nozzle between cell and gel, lifted with electrical-controlled lifting platform courses shower nozzle, 3D printing
Two shower nozzles of machine successively printing alternate urethra section.By in vitro culture fat-derived stem cells, it is induced to be divided on urinary tract
Chrotoplast and smooth muscle cell, cell drop is then converted into, with reference to 3D printing, rebuilds urethra in vitro, then will rebuild again
Urethra be transplanted to patient with it go.That is, the 3D biometric prints material used in above-mentioned existing 3D biometric prints technology is two
Kind：One kind is to wrap celliferous bio-ink, a kind of timbering material for being used as support.
Prior art is basically to find suitable bio-ink and timbering material, example on the research direction of 3D printing
Such as：The A of CN 104399119 disclose a kind of method that strong mechanical performance cartilage is prepared based on 3D biometric prints, and it passes through silk
Fiber and gelatin solution prepare the bio-ink containing cartilage stem cell, and forming support with PCL materials, (PCL is a kind of semicrystalline
Polymer, it is [CH that structure, which is made, by 6-caprolactone titanium catalyst, dihydroxy or the ring-opening polymerisation of trihydroxy initiator2-(CH2)4-
COO]nPolyester).Contain phosphate buffer, Sodium Alginate, gelatin, methacrylic acid anhydride solution, two water wherein in bio-ink
Calcium sulfate, silk fiber and UV light triggers are closed, ionic bond, gelatin and metering system are formed by Sodium Alginate and calcium ion
Acid anhydrides forms the mechanical property that covalent bond improves gel, and printing is molded after completing by UV light irradiations.For another example：CN
A kind of bio-ink for 3D printing is disclosed in 105238132 A, its constituent is included with the water-soluble of crosslinking function
Property synthetic polymer, there is the water-soluble natural macromolecule of crosslinking function, the bioactivity of special ultra microstructure can be spontaneously formed
Component, cross-linked evocating agent and solvent, further comprise biological active component；Ink is finally solidified into again by UV light irradiations
Type.The A of CN 105885436 disclose a kind of bio-ink material for 3D printing and its preparation method and application, and this is existing
Technology provides timbering material in fact, and the timbering material is used as support ink by the use of large biological molecule, precrosslinker, coagulant
Material, shape after printing by washing, crosslinking agent, acquisition is antigenic, rejection is small and has biodegradability
Soft tissue support.
Described above is the background of the 3D biometric print technologies comprising support, disclosed in the A of CN 103249567
Be used for manufacture in the devices, systems, and methods of tissue, for the various materials of 3D biometric prints component carried out it is detailed
Enumerate, wherein specifically mentioned prior art also whether there is the trial of support 3D biometric print technologies, but exist very without support technology
More limitations, such as be difficult to obtain complicated geometry, be difficult to be formed blood vessel network of nutrient etc. needed for offer tissue production.Cause
This, what the prior art provided is the 3D biometric print solutions comprising support.
In fact a very thin layer tissue can only be printed just because of above-mentioned reason, existing 3D biometric prints technology, because
For compared with, without nutrition channels such as blood vessels, internal cell is difficult to acquisition nutriment inside thick tissue, metabolite can not discharge,
Thus thicker 3D printing tissue is difficult to Sustainable Growth.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of degradable 3D printing bio-ink of temperature-responsive and 3D to beat
Impression method, so that the problem of being formerly mentioned is reduced or avoided.
Specifically, the invention provides a kind of degradable 3D printing bio-ink of temperature-responsive and 3D printing method,
It can print the model without support support obtained containing biological cell, and can also further obtain porous model,
It can be produced for cell and nutrition and metabolism passage is provided, be advantageous to obtain bigger thicker institutional framework by 3D printing.
In order to solve the above technical problems, the present invention proposes a kind of degradable 3D printing bio-ink of temperature-responsive, by
Hydrogel and biological cell are formed, wherein, the hydrogel is made up of following component：The PLGA- of mass fraction 10%~40%
PEG-PLGA triblock copolymers, the Porcine HGF of mass fraction 0.001%~1%, mass fraction 0.05~0.3%
Anti-inflammation hemostasia medicine, surplus are deionized water.
Further, present invention also offers a kind of preparation side of the degradable 3D printing bio-ink of said temperature response
Method, comprise the following steps：By PLGA-PEG-PLGA triblock copolymers, the mass fraction of mass fraction 10%~40%
0.001%~1% Porcine HGF, the anti-inflammation hemostasia medicine of mass fraction 0.05~0.3% and the deionized water of surplus
Blending, 30min is stirred, stand 1~6 hour and the hydrogel is made；The hydrogel is uniformly mixed with the biological cell
Into the 3D printing bio-ink.
In addition, present invention also offers a kind of 3D printing using the degradable 3D printing bio-ink of said temperature response
Method, comprise the following steps：
Step A：Using the degradable 3D printing bio-ink of said temperature response, in the temperature conditionss less than phase in version
Under, add soybean protein isolate solution and stir, then add calcium sulphate soln and be uniformly mixed into standby 3D printing material；
Step B：The ink storehouse temperature of control 3D biometric print machines is less than phase transition temperature, and printing table top temperature is 37 Celsius
Degree, by 3D printing shower nozzle by the 3D printing file printing into model.
Preferably, in the step A, the biological cell is before the 3D printing bio-ink is prepared, to the life
Thing cell carries out protection processing：The starch solution that the glycerine and concentration for being 10% with concentration by the biological cell are 10% is equal
Even mixing stands 2-3 hours.
Preferably, the above method can further include following steps：
Step C：The model is placed in temperature control box, the temperature in the temperature control box is slowly reduced to less than 0 degree, makes institute
The moisture stated in model freezes completely；
Step D：The temperature in the temperature control box is quickly raised to 37 degrees Celsius, makes the hydrogel in the model completely solid
Change, so as to obtain the porous structural model containing biological cell.
Preferably, in the step C, temperature in the temperature control box is slowly reduced to zero with the speed of 4-5 degree per hour
15 are descended to minus 20 degrees.
Preferably, in the step D, 37 degree of dry-heat air is conveyed into the temperature control box, makes the ice in the model
Rapid translating escapes into gas from the model, so as to form loose structure on the model.
Preferably, methods described further comprises, is obtaining the porous structural model containing biological cell
Afterwards, vascular endothelial cell is injected in the loose structure, the vascular endothelial cell is attached on structure pore framework,
The model is placed in nutritive solution afterwards and cultivated, blood vessel, the model are gone out by the vascular endothelial cell growth
In original cell growth into required tissue, the blood vessel grown further provides nutrient for required tissue and metabolism is logical
Road.
Preferably, methods described further comprises：Obtaining the porous structural model containing biological cell
Afterwards, the model is uniformly got to the parallel via holes of insertion by laser, for the hole connection in model to be got up, then
Vascular endothelial cell is injected in the loose structure, the vascular endothelial cell is attached on structure pore framework, afterwards
The model is placed in nutritive solution and cultivated, blood vessel, the model Central Plains are gone out by the vascular endothelial cell growth
For some cell growths into required tissue, the blood vessel grown further provides nutrient and metabolic pathway for required tissue.
The degradable 3D printing bio-ink of temperature-responsive of the present invention is made up of hydrogel and biological cell, the water-setting
Glue by the PLGA-PEG-PLGA triblock copolymers with temperature-responsive according to a certain percentage with other additives, such as carefully
The intracellular growth factor and anti-inflammation hemostasia medicine and deionized water are mixed, because the PLGA-PEG-PLGA tri- of temperature-responsive is embedding
The critical inversion temperature scope of section copolymer is 20-33 DEG C, has and is solidified into gel characteristic in 37 DEG C of body temperature, so as to
So that the 3D printing bio-ink of the present invention possesses same temperature-responsive and degradable characteristic.The present invention utilizes above-mentioned 3D
The temperature-responsive of bio-ink and degradable characteristic are printed, the bio-ink of pre-agglomeration is prepared before the printing, prints it
Afterwards to the abjection moisture that is rapidly heated after the slow freezing of model, the porous structural model containing biological cell can be formed, can
To obtain the nutrition and metabolism passage of loose structure, be advantageous to obtain bigger thicker institutional framework by 3D printing.
Embodiment
In order to which technical characteristic, purpose and the effect of the present invention is more clearly understood, now pass through the specific of the present invention
Embodiment is described in detail.
Just as described in the background section, no matter existing 3D biometric prints technology selects what kind of bio-ink or support
Material, the defects of being difficult to overcome the tissue of printing acquisition to lack nutrition and metabolism passage.Therefore, the invention provides a kind of new
3D printing method, it can be obtained the model supported without support containing biological cell by 3D printing, and can also entered
One step obtains porous model, can be produced for cell and provide nutrition and metabolism passage, is advantageous to bigger by 3D printing acquisition
Thicker institutional framework.
Specifically, the present invention provides a kind of 3D printing method, comprises the following steps：
Step A：A kind of 3D printing bio-ink being made up of hydrogel and biological cell is provided, less than phase transition temperature
Under conditions of, add soybean protein isolate solution and stir, then addition calcium sulphate soln is uniformly mixed into standby 3D and beaten
Print material.
Wherein, the 3D printing bio-ink can be any existing 3D being made up of hydrogel and biological cell
Bio-ink is printed, preferably described 3D printing bio-ink is the life that its character is suitable for being printed using 3D biometric print machines
Thing ink.
Particularly preferably, the 3D printing bio-ink is to be exclusively used in the material of the 3D printing method of the present invention, and it is by water-setting
Glue and biological cell are formed.
3D printing bio-ink example 1
Present example provides a kind of 3D printing bio-ink for the 3D printing method for being exclusively used in the present invention, its by hydrogel and
Biological cell is formed, wherein the hydrogel is made up of following component：Cross-linked-hyaluronic acid, NIPA
(PNIPAAm), poly- (N, N- acrylamide) (PDEAAm), poly- (2- carboxy-Ns-N-isopropylacrylamide)
(PCIPAAm), polymethyl vinyl ether, polyethylene glycol ethylene oxide (PEG-PEO) and deionized water.
In a specific embodiment, the hydrogel can use following component to form：The crosslinking of mass fraction 1% is saturating
Bright matter acid, the NIPA of mass fraction 3%, mass fraction 3% poly- (N, N- acrylamide),
Poly- (the 2- carboxy-Ns-N-isopropylacrylamide) of mass fraction 1%, the polymethyl vinyl ether of mass fraction 3%, mass fraction
3% PEG-PEO and the deionized water that surplus is mass fraction 86%.
In another specific embodiment, the hydrogel can use following component to form：The crosslinking of mass fraction 5%
Hyaluronic acid, the NIPA of mass fraction 5%, poly- (N, N- the diethyl acryloyl of mass fraction 5%
Amine), poly- (2- carboxy-Ns-N-isopropylacrylamide), the polymethyl vinyl ether of mass fraction 5%, the quality of mass fraction 3%
The PEG-PEO of fraction 5% and the deionized water that surplus is mass fraction 72%.
In another specific embodiment, the hydrogel can use following component to form：The crosslinking of mass fraction 3%
Hyaluronic acid, the NIPA of mass fraction 4%, poly- (N, N- the diethyl acryloyl of mass fraction 4%
Amine), poly- (2- carboxy-Ns-N-isopropylacrylamide), the polymethyl vinyl ether of mass fraction 4%, the quality of mass fraction 2%
The PEG-PEO of fraction 4% and the deionized water that surplus is mass fraction 79%.
In an also specific embodiment, the hydrogel can use following component to form：The friendship of mass fraction 1%
Join hyaluronic acid, the NIPA of mass fraction 4%, poly- (N, N- the diethyl acryloyl of mass fraction 4%
Amine), poly- (2- carboxy-Ns-N-isopropylacrylamide), the polymethyl vinyl ether of mass fraction 4%, the quality of mass fraction 2%
The PEG-PEO of fraction 5% and the deionized water that surplus is mass fraction 80%.
Further, present invention also offers the preparation method of 3D printing bio-ink described in example 1, including following step
Suddenly：By mass fraction 1%-5% cross-linked-hyaluronic acid, mass fraction 3%-5% NIPA, quality
Fraction 3%-5% poly- (N, N- acrylamide), mass fraction 3%-5% polymethyl vinyl ether, mass fraction
3%-5% polyethylene glycol ethylene oxide (PEG-PEO) is blended with the deionized water of surplus, stirs 30min, stands 1~6
The hydrogel is made in hour；The hydrogel and the biological cell are uniformly mixed into the 3D printing bio-ink.
3D printing bio-ink example 2
The 3D printing bio-ink of the 3D printing method of the present invention, the 3D printing are exclusively used in present example provides another kind
Bio-ink is a kind of degradable 3D printing bio-ink of temperature-responsive, and it is made up of hydrogel and biological cell, wherein institute
Hydrogel is stated to be made up of following component：PLGA-PEG-PLGA triblock copolymers, the mass fraction of mass fraction 10%~40%
0.001%~1% Porcine HGF, the anti-inflammation hemostasia medicine of mass fraction 0.05~0.3%, surplus are deionized water.
Wherein, PLGA-PEG-PLGA triblock copolymers can be poly- by poly (lactic acid-glycolic acid) (PLGA) and polyethylene glycol (PEG)
Close and formed, have application carrying medicine and slow releasing pharmaceutical field, for example, proposing one in Chinese patent application 2015103092137 more
The purposes of kind PLGA-PEG-PLGA triblock copolymers in medicine and slow releasing pharmaceutical is carried and preparation method thereof, from the prior art
It can obtain molten available for the PLGA-PEG-PLGA triblock copolymers for carrying medicine and slow releasing pharmaceutical, the load medicine of the triblock copolymer
Liquid can with temperature raise occur solution-gel phase in version, phase transition temperature be 35~39 DEG C, and the copolymer also have can
Biodegradation character.Load drug solns prepared by the above-mentioned PLGA-PEG-PLGA triblock copolymers proposed in the prior art, work as temperature
When degree is less than phase transition temperature, it is changed into solution state；It can then be changed into gel state when temperature reaches phase transition temperature.Therefore drug solns are carried
It is stored in and is less than under the conditions of human body temperature suitable for being injected in solution state, after being expelled to human body, reaches phase transition temperature and then can
It is changed into gel state, suitable for carrying out degraded release medicine in gel state.
Therefore, temperature-responsive and degradable characteristic of the present invention using PLGA-PEG-PLGA triblock copolymers, it is special
A kind of a kind of new application of PLGA-PEG-PLGA triblock copolymers is not proposed, is prepared and obtained using the triblock copolymer
The 3D printing bio-ink of the present invention can be exclusively used in by obtaining, and the 3D printing bio-ink is by PLGA-PEG-PLGA triblock copolymers
Hydrogel and biological cell form.It will be appreciated by those skilled in the art that relevant PLGA-PEG-PLGA triblock copolymers
Prepare and characteristic is referred to above-mentioned prior art or other existing pertinent literatures, can also be adjusted and made according to prior art
The scheme of the standby triblock copolymer, to obtain suitable phase transition temperature, these are not the scope of protection of the invention, this hair
Bright focus of attention is the temperature-responsive and degradable characteristic for existing PLGA-PEG-PLGA triblock copolymers,
Propose application of the triblock copolymer in 3D printing bio-ink field.
Porcine HGF is a kind of protein molecule that various types of cells can be promoted to breed, and has chemotactic, propagation and reconstruction
Effect, it can induce the target cells such as fibroblast, epithelial cell, vascular endothelial cell in inflammatory phase and moved to damage location, repaiied
Multiple damaged portion；It can promote epithelial cell, vascular endothelial cell, fibroblast proliferation in proliferation period growth factor, promote fine
Tie up cellular rearrangements；The healing of phase acceleration of wound is being rebuild, cicatrization is being reduced, for bone, joint and neurotrosis, cell growth factor
Son can promote skin, hypodermis, bone tissue reparation and blood vessel, nerve reconstructive, promote new vessels generation, nerve cell and bone group
Regeneration is knitted, is served in terms of wound healing considerable.
Porcine HGF has basic fibroblast growth factor, EGF, IGF, nerve
Trophic factors, TGF, keratinocyte growth factor, platelet derived growth factor etc..
Basic fibroblast growth factor promotes cell division propagation and Angiogensis, is to be currently known most strong rush
The Hemapoiesis factor.It is fibroblast, epithelial cell, vascular endothelial cell, Skeletal Muscle Cell, cartilage cell, Gegenbaur's cell, flat
Sliding myocyte, neuron, Deiter's cells, lens epithelial cells, corneal epithelial cell, adrenal cortex medullary epithelium are
The recipient cell of basic fibroblast growth factor.
EGF is synthesized by monocyte and ectoderm cell, stimulate the division of internal polytype histocyte and
Propagation, enhancing signaling, merisis and the generation of cytoplasm albumen, such as skin, cornea, lung, tracheae and liver regeneration.
IGF is by two close phases of type-1 insulin like growth factor type and IMA-IGF2BP3-001 type
The family of the small polypeptide composition closed, has and promotes muscle protein synthesis, promotes propagation, the differentiation of sarcoblast, participates in tissue and repair
Multiple and regeneration, so as to accelerate organization healing.
The trace soluble material that neurotrophic factor is present in around sensory neuron, produced by the target cell of neuron
It is raw, specifically promote neure growth and maintenance, promotion organization injury repair.
Porcine HGF is introduced into hydrogel by the present invention, and advantage is in can give in the bio-ink of subsequent configuration
Cells with nutrient.Support is printed with 3D printing technique, after stenter to implant human body, cell factor can promote hydrogel
Cell differentiation, increment on support, accelerate tissue reconstruction.
Sulfa drugs such as sulfapryidine silver, mafenide etc.；QNS such as Enoxacin, Norfloxacin, oxygen
Flucloxacillin etc. has antibacterial and anti-inflammation functions.Haemostatic medicament such as adrenobazonum, etamcylate, tranxamic acid, road fourth etc., which have, accelerates blood coagulation
Effect.
In a specific embodiment, the hydrogel can use following component to form：The PLGA- of mass fraction 30%
PEG-PLGA triblock copolymers, the basic fibroblast growth factor of mass fraction 0.01%, the sulphur of mass fraction 0.05%
Amine pyridine silver, surplus are deionized water.
In another specific embodiment, the hydrogel can use following component to form：Mass fraction 10%
PLGA-PEG-PLGA triblock copolymers, the epithelical cell growth factor of mass fraction 1%, the promise fluorine of mass fraction 0.2% are husky
Star, surplus are deionized water.
In another specific embodiment, the hydrogel can use following component to form：Mass fraction 15%
PLGA-PEG-PLGA triblock copolymers, the keratinocyte growth factor of mass fraction 0.05%, the peace of mass fraction 0.25%
Network blood, surplus are deionized water.
In an also specific embodiment, the hydrogel can use following component to form：Mass fraction 20%
PLGA-PEG-PLGA triblock copolymers, the IGF of mass fraction 0.5%, the sulfanilamide (SN) of mass fraction 0.3%
Myron and etamcylate, surplus are deionized water.
In an also specific embodiment, the hydrogel can use following component to form：Mass fraction 40%
PLGA-PEG-PLGA triblock copolymers, the neurotrophic growth factor of mass fraction fraction 0.001%, mass fraction
0.15% Ofloxacin and Lu Ding, surplus are deionized water.
Further, present invention also offers the preparation of the degradable 3D printing bio-ink of temperature-responsive described in example 2
Method, comprise the following steps：By PLGA-PEG-PLGA triblock copolymers, the mass fraction of mass fraction 10%~40%
0.001%~1% Porcine HGF, the anti-inflammation hemostasia medicine of mass fraction 0.05~0.3% and the deionized water of surplus
Blending, 30min is stirred, stand 1~6 hour and the hydrogel is made；The hydrogel is uniformly mixed with the biological cell
Into the degradable 3D printing bio-ink of the temperature-responsive.
Particularly, in Method of printing of the invention, before 3D printing is carried out, control temperature turns 3D printing material less than phase
Temperature, now solution is to be in a kind of collosol state of low sticky degree, approximate colloid, by adding soybean protein isolate solution
Stirring, a little calcium sulphate soln is then added, such as the concentration of addition stoste (3D printing material) volume 10% is 5% soybean
Protein isolate solution, the concentration for adding stoste volume 1%-2% is 5-8% calcium sulphate soln, is neutralized by sulfuric acid calcium ion
The electric charge of colloid absorption makes colloid trigger cohesion.It is emphasized that this process needs to match somebody with somebody within 15-30 minutes before the printing
Put, to prevent coacervation of colloid solidification to be difficult to print.
Completed it needs to be emphasized that step A of the invention is preferably configured within 15-30 minutes before the printing, and
Printed and completed by printing head in subsequent 15-30 minutes, the bio-ink otherwise configured easily condenses solidification and blocks shower nozzle.
In addition, the biological cell suitable for the present invention can be any vertebrate cells, mammalian cell, people
Cell or its combination, its type depend on produced cell construction body, tissue or organ type.Such as the cell can
With including be not limited to for shrinkage cell or muscle cell, phoirocyte, bone marrow cell, endothelial cell, Skin Cell,
Epithelial cell, mammary glandular cell, vascular cell, haemocyte, lymphocyte, nerve cell, gastrointestinal tract cell, liver cell, pancreas are thin
Born of the same parents, pneumonocyte, tracheal cell, keratocyte, urogenital cell, nephrocyte, reproduction cell, adipocyte, mesothelial cell,
Cell plastid, entoderm source cell, mesoderm source cell, ectoderm source cell and combinations thereof.In a preferred embodiment, it is described
Cell is stem cell, including but not limited to embryonic stem cell, adult stem cell, amnion stem cell and inductive pluripotent stem cells
Deng.Wherein the addition of biological cell is added according to the difference of different tissues, the speed of growth.
It should be noted that hydrogel specifically preferred according to the invention has temperature-responsive, its critical inversion temperature model
Enclose for 20-33 degrees Celsius, when less than phase transition temperature, solution is in low sticky approximation colloidal state.Higher than phase transition temperature
When, such as 34-37 degrees Celsius, or even to 40 degrees Celsius, hydrogel can be undergone phase transition, and gradually cohesion solidification, that is, be had in human body
37 DEG C of body temperature is solidified into gel characteristic.When adding soy bean proteinous soln and calcium sulphate soln, it is necessary to maintain the temperature at phase alternating temperature
Carried out in the range of degree.Because hydrogel has temperature-responsive, the bio-ink subsequently mixed also has temperature-responsive.
It is preferred that phase transition temperature is 25-32 degrees Celsius.More preferably 28-31 degrees Celsius.
Standby 3D printing material is formd in the step A of the 3D printing method of the present invention, can be entered afterwards according to step B
The further operation of row.
Step B：The ink storehouse control temperature of control 3D biometric print machines is less than phase transition temperature, printing table top control temperature
For 37 degrees Celsius, using the temperature-responsive of bio-ink, the bio-ink is printed as by model by 3D printing shower nozzle.This
In step, 3D printer can be suitable for the printer of organism 3D printing using existing any one, wherein foregoing standby
3D printing material is placed in ink storehouse, and temperature keeps below phase transition temperature, makes the character of 3D printing material stably be easy to print
And shower nozzle is not easily blocked, and the 3D printing shower nozzle of printer can be set in temperature control box, and the stamp pad in temperature control box
Printing forms model on face.Now, it is 37 degrees Celsius to control the temperature in temperature control box so that model being capable of solidifying and setting.
It should be noted that soybean protein isolate is with the addition of in abovementioned steps is molten for bio-ink specifically preferred according to the invention
Liquid and calcium sulphate soln have carried out pre-agglomeration, condense solidification after being printed as model.The change and the regulation and control of time of temperature make biology
Ink possesses two kinds of coacervation processes, and when being printed to by printing head on temperature control box printing table top, the droplet printed every time is very
Fixed structure is easily formed, thus the above-mentioned particularly preferred bio-ink of the present invention can need not print one layer and cover afterwards
One layer of timbering material is supported, there is provided one kind is without support 3D biometric print technologies.Namely pass through the above-mentioned 3D of the present invention
The step A and step B of Method of printing, the 3D printing model without support support can be directly obtained on the basis of hydrogel, can
To save the time-write interval of support, without changing printhead, can save time-write interval and cost.
Certainly, be not precluded from can be by existing 3D printer successively printing alternate bio-ink and support material by the present invention
Material forms the technical scheme of model, i.e. in order to form the model structure of complexity, in a preferred embodiment, this step enters one
Step is included in the bio-ink and the timbering material successively printing alternate into model in temperature control box by 3D printing shower nozzle,
To provide support to bio-ink by timbering material.Wherein, the timbering material can be selected from any existing suitable
For the timbering material of 3D printing, including it is not limited to fibrin, alginates, agarose, chitosan and combinations thereof.
Further, the present invention can also be right on the basis of above-mentioned steps A and step B by following additional step
Model carries out subsequent treatment, to generate a kind of porous model structure.
Step C：The model is placed in temperature control box (if model is directly printed upon in temperature control box, can omit by
Model inserts the step of temperature control box), the temperature in the temperature control box is slowly reduced to less than 0 degree, makes the moisture in the model
Freeze completely.The effect of this step is the water in model is build-up ice by cooling, expands 10% from the water volume of maximal density,
By big hole of the formation containing ice of support inside the jellium model of cohesion.Should it is especially mentioned that, the process of cooling needs very slow
Slowly, it is ensured that by liquid slow coagulation, water in model structure is dispersed to congeal into ice, and keeps model as far as possible for water in model
Internal structure, the too fast meeting that otherwise cools cause model overall structure to destroy, are difficult to keep tissue morphology after ice-out.It is preferred that
In this step, temperature in the temperature control box is slowly reduced to subzero 15 to minus 20 degrees with the speed of 4-5 degree per hour.
It should be strongly noted that when temperature is reduced to subzero, if not doing protection processing, contain in biological cell
Moisture can also freeze, the ice crystal of formation can the basic structure of damaging cells cause biological cell loss of activity.Therefore, to carry out
Step C refrigerating process is, it is necessary in foregoing step A, before biological cell is prepared into 3D printing bio-ink, to life
Thing cell carries out protection processing：The starch solution that the glycerine and concentration for being 10% with concentration by biological cell are 10% uniformly mixes
Close and stand 2-3 hours.The effect of this step is to be wrapped up biological cell using the colloid of starch solution, is reduced using glycerine
The freezing point of moisture in biological cell, under the conditions of step C slow freezing, ICW appears, and reduces ice crystal and is formed,
So as to avoid cellular damage, ensure biological cell survival.In a specific embodiment, the glycerine of concentration 10% and concentration are
The addition of 10% starch solution can be respectively 1-1.5 times and 0.5-0.8 times of biological cell quality.
In addition, the temperature-fall period of the present invention will not also cause model to cave in.Bio-ink of the present invention has two kinds and condensed
Journey, it is a kind of be 3D printing material temperature-responsive cohesion, it is a kind of be the time-controllable added after soybean protein and calcium sulfate
Cohesion.In temperature-fall period, moisture can be very good to seek connections with soybean protein and calcium sulfate cohesion 3D biomaterials before freezing
On the skeleton of formation, it is unlikely to cave in.
Step D：The temperature in the temperature control box is quickly raised to 37 degrees Celsius, makes the hydrogel in the model completely solid
Change, so as to obtain the porous structural model containing biological cell.In this step, model slow cooling to subzero 15 to subzero 20
After degree, in the case where model volume is generally little, the water in model all condenses, now can be by being rapidly heated
To 37 degree of organism active temperature, the hydrogel in model is set to solidify again, while the ice-out in model, in gel solidification
During moisture deviate from, the hole containing ice can remain in the gel structure of solidification, so as to form containing biological cell
Loose structure.
Particularly, the temperature-rise period in this step is different from foregoing temperature-fall period, it is necessary to which lift scheme temperature makes as early as possible
Obtain structure as early as possible to solidify, avoid solidification from slowly causing hole to disappear.In a preferred embodiment, can be to institute in this step
The dry-heat air of 37 degree of conveying in temperature control box is stated, the ice rapid translating in the model is escaped into gas from the model, from
And form loose structure on the model.Dry-heat air can lift temperature in temperature control box quickly to 37 degree, dry simultaneously
Hot blast has discharged the moisture in temperature control box, reduces water vapor partial pressure, has further speeded up the speed that moisture is converted into gas, thus
The present embodiment can reach the effect for making model be formed by curing loose structure as early as possible.
After the loose structure containing biological cell obtained on model, model can be placed in nutritive solution and carried out
Culture, because loose structure is that biological cell provides and obtains the passage of nutrition and metabolism, thus cell inside model is the same as outside
Portion's cell equally can obtain enough nutrient growth, can be obtained by this 3D printing method of the present invention bigger thicker
Institutional framework.
In order to avoid institutional framework growth closure after, internal cell easily lack nutrient, metabolism it is not smooth and dead, another
In one preferred embodiment, after the porous structural model containing biological cell is obtained, injected in the loose structure
Vascular endothelial cell, vascular endothelial cell is attached on structure pore framework, model is placed in nutritive solution carried out afterwards
Culture, goes out blood vessel, original cell growth is into required tissue in model, the blood vessel grown by vascular endothelial cell growth
Further nutrient and metabolic pathway are provided for required tissue.Further, in order to avoid the hole inside loose structure does not connect
It is logical, the defects of causing the blood vessel of growth to be difficult to insertion, in another preferred embodiment, biological cell can be contained obtaining
After porous structural model, the model is uniformly got to the parallel via holes of insertion by laser, for by the hole in model
Hole connection is got up.Laser boring obtain through-hole diameter it is limited, be appropriate only for by hole connection be easy to vascular endothelial cell and
Nutrient solution enters inner void, is operated according to aforesaid way thereafter, vascular endothelial cell is injected in loose structure, is made intravascular
Chrotoplast is attached on structure pore framework, model is placed in nutritive solution cultivated afterwards, pass through vascular endothelial cell
Grow blood vessel.With the growth of blood vessel and tissue, the through hole for these insertions that laser boring obtains can be stretched, when
So, adequate thickness and the tissue of volume are obtained, or the main porous structure mould for needing to obtain in dependence previous embodiment
Type.
In summary, the degradable 3D printing bio-ink of temperature-responsive of the invention is by hydrogel and biological cell structure
Into the hydrogel is added with other according to a certain percentage by the PLGA-PEG-PLGA triblock copolymers with temperature-responsive
Thing, such as Porcine HGF and anti-inflammation hemostasia medicine and deionized water is added to be mixed, due to the PLGA- of temperature-responsive
The critical inversion temperature scope of PEG-PLGA triblock copolymers is 20-33 DEG C, has being solidified into 37 DEG C of body temperature
Gel characteristic, so that the 3D printing bio-ink of the present invention possesses same temperature-responsive and degradable characteristic.This
Temperature-responsive and degradable characteristic of the invention using above-mentioned 3D printing bio-ink, the life of pre-agglomeration is prepared before the printing
Thing ink, to the abjection moisture that is rapidly heated after the slow freezing of model after printing, it can be formed containing the porous of biological cell
Structural model, the nutrition and metabolism passage of loose structure can be obtained, be advantageous to obtain bigger thicker group by 3D printing
Knit structure.
It will be appreciated by those skilled in the art that although the present invention is described in the way of multiple embodiments,
It is that not each embodiment only includes an independent technical scheme.So narration is used for the purpose of for the sake of understanding in specification,
The skilled in the art should refer to the specification as a whole is understood, and by technical scheme involved in each embodiment
The modes of different embodiments can be mutually combined into understand protection scope of the present invention by regarding as.
The schematical embodiment of the present invention is the foregoing is only, is not limited to the scope of the present invention.It is any
Those skilled in the art, equivalent variations, modification and the combination made on the premise of the design of the present invention and principle is not departed from,
The scope of protection of the invention all should be belonged to.
Claims (7)
1. a kind of degradable 3D printing bio-ink of temperature-responsive, is made up of, it is characterised in that institute hydrogel and biological cell
Hydrogel is stated to be made up of following component：PLGA-PEG-PLGA triblock copolymers, the mass fraction of mass fraction 10%~40%
0.001%~1% Porcine HGF, the anti-inflammation hemostasia medicine of mass fraction 0.05~0.3%, surplus are deionized water.
2. a kind of preparation method of the degradable 3D printing bio-ink of temperature-responsive as claimed in claim 1, including it is as follows
Step：By the PLGA-PEG-PLGA triblock copolymers of mass fraction 10%~40%, mass fraction 0.001%~1% it is thin
The deionized water blending of the intracellular growth factor, the anti-inflammation hemostasia medicine of mass fraction 0.05~0.3% and surplus, stirs 30min, quiet
Put 1~6 hour and the hydrogel is made；The hydrogel and the biological cell are uniformly mixed into the temperature-responsive can
Degraded 3D printing bio-ink.
3. a kind of 3D printing method of degradable 3D printing bio-ink of temperature-responsive using described in claim 1, including
Following steps：
Step A：Using the degradable 3D printing bio-ink of temperature-responsive described in claim 1, in the temperature less than phase in version
Under the conditions of degree, add soybean protein isolate solution and stir, then addition calcium sulphate soln is uniformly mixed into standby 3D and beaten
Print material；
Step B：The ink storehouse temperature of control 3D biometric print machines is less than phase transition temperature, and printing table top temperature is 37 degrees Celsius,
By 3D printing shower nozzle by the 3D printing file printing into model.
4. method as claimed in claim 3, it is characterised in that in the step A, the biological cell is beaten preparing the 3D
Before printing bio-ink, protection processing is carried out to the biological cell：By glycerine that the biological cell and concentration are 10% with
And the starch solution that concentration is 10% uniformly mixes and stands 2-3 hours.
5. method as claimed in claim 4, further comprises following steps：
Step C：The model is placed in temperature control box, the temperature in the temperature control box is slowly reduced to less than 0 degree, makes the mould
Moisture in type freezes completely；
Step D：The temperature in the temperature control box is quickly raised to 37 degrees Celsius, the hydrogel in the model is fully cured,
So as to obtain the porous structural model containing biological cell.
6. 3D printing method as claimed in claim 5, it is characterised in that in the step C, with the speed of 4-5 degree per hour
Temperature in the temperature control box is slowly reduced to subzero 15 to minus 20 degrees.
7. 3D printing method as claimed in claim 5, it is characterised in that in the step D, 37 are conveyed into the temperature control box
The dry-heat air of degree, the ice rapid translating in the model is set to be escaped into gas from the model, so as to the shape on the model
Into loose structure.
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| CN201710790405.3A Active CN107523136B (en) | 2016-12-09 | 2017-09-05 | Temperature-responsive degradable 3D printing biological ink and 3D printing method |
| CN201710790440.5A Active CN107502061B (en) | 2016-12-09 | 2017-09-05 | Superficial degradation type 3D printing bio-ink and 3D printing method |
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| CN114395930A (en) * | 2021-12-31 | 2022-04-26 | 山东中康国创先进印染技术研究院有限公司 | Direct injection type reactive dye ink used for printed fabric and free of front and back treatment and application thereof |
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Also Published As
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| CN107400412B (en) | 2018-08-24 |
| CN107502061B (en) | 2018-08-24 |
| CN107523136B (en) | 2020-01-14 |
| CN107400412A (en) | 2017-11-28 |
| CN107502061A (en) | 2017-12-22 |
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