CN107875444A - Preparation method for the hydrogel scaffold material of the biological degradability of cardiac repair - Google Patents
Preparation method for the hydrogel scaffold material of the biological degradability of cardiac repair Download PDFInfo
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- 239000000463 material Substances 0.000 title claims abstract description 40
- 239000000017 hydrogel Substances 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 230000000747 cardiac effect Effects 0.000 title claims abstract description 12
- 230000008439 repair process Effects 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 239000000499 gel Substances 0.000 claims description 20
- 229920001223 polyethylene glycol Polymers 0.000 claims description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 14
- 229920000428 triblock copolymer Polymers 0.000 claims description 10
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000002243 precursor Substances 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000002202 Polyethylene glycol Substances 0.000 claims description 8
- 239000008363 phosphate buffer Substances 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 239000006228 supernatant Substances 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 5
- 229920000642 polymer Polymers 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- -1 Hydrogen furans Chemical class 0.000 claims description 4
- 238000013019 agitation Methods 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 230000008014 freezing Effects 0.000 claims description 4
- 238000007710 freezing Methods 0.000 claims description 4
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000005474 octanoate group Chemical group 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 238000007789 sealing Methods 0.000 claims description 4
- 238000012360 testing method Methods 0.000 claims description 4
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 claims description 4
- 238000002604 ultrasonography Methods 0.000 claims description 4
- 238000005119 centrifugation Methods 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 2
- 239000000178 monomer Substances 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 claims description 2
- 230000001900 immune effect Effects 0.000 abstract description 5
- 210000000056 organ Anatomy 0.000 abstract description 4
- 208000019622 heart disease Diseases 0.000 abstract description 3
- 239000012567 medical material Substances 0.000 abstract description 2
- 238000002054 transplantation Methods 0.000 abstract description 2
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- 239000000243 solution Substances 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 10
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 210000005003 heart tissue Anatomy 0.000 description 5
- 230000008901 benefit Effects 0.000 description 4
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- 239000003431 cross linking reagent Substances 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000010146 3D printing Methods 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 238000007639 printing Methods 0.000 description 3
- 238000007711 solidification Methods 0.000 description 3
- 230000008023 solidification Effects 0.000 description 3
- KWVGIHKZDCUPEU-UHFFFAOYSA-N 2,2-dimethoxy-2-phenylacetophenone Chemical class C=1C=CC=CC=1C(OC)(OC)C(=O)C1=CC=CC=C1 KWVGIHKZDCUPEU-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 230000021164 cell adhesion Effects 0.000 description 2
- 238000001723 curing Methods 0.000 description 2
- 238000004134 energy conservation Methods 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 238000003848 UV Light-Curing Methods 0.000 description 1
- 229920003232 aliphatic polyester Polymers 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000012650 click reaction Methods 0.000 description 1
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- 239000003292 glue Substances 0.000 description 1
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- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
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- 239000007924 injection Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
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- 229920000728 polyester Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 1
- 210000000717 sertoli cell Anatomy 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000009331 sowing Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
Classifications
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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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—Hydrogels or hydrocolloids
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
- C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/91—Polymers modified by chemical after-treatment
- C08G63/912—Polymers modified by chemical after-treatment derived from hydroxycarboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
-
- 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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/20—Materials or treatment for tissue regeneration for reconstruction of the heart, e.g. heart valves
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2367/00—Characterised by the use of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Derivatives of such polymers
- C08J2367/04—Polyesters derived from hydroxy carboxylic acids, e.g. lactones
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- Life Sciences & Earth Sciences (AREA)
- Oral & Maxillofacial Surgery (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Transplantation (AREA)
- Dispersion Chemistry (AREA)
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Abstract
The present invention relates to biology medical material technical field, and in particular to a kind of preparation method of the hydrogel scaffold material of biological degradability for cardiac repair.To solve the problems such as immunological rejection caused by traditional heteroplastic transplantation method treatment heart disease and donor organ wretched insufficiency.The step of preparation method that technical solution of the present invention uses for：1）PVL PEG PVL preparation；2）It is modified；3）Prepare hydrogel scaffold material.
Description
Technical field
The present invention relates to biology medical material technical field, and in particular to a kind of biological degradability for cardiac repair
The preparation method of hydrogel scaffold material.
Background technology
Heart disease has very high morbidity and mortality in clinical medicine, accounts for the 12% of the global death rate.It is thus tight
The existence that threaten the world today mankind health of weight, and serious influence is caused to the life of people.It is in those early years to use more
The method of ventricular assist device and the method for Heterotopic Heart Transplant treat impaired heart area, but use the ventricle auxiliary to set
Larger size, structure and the problems such as control is complicated, equipment failure rate is high be present in standby method.Although the method for Heterotopic Heart Transplant
The patient of middle and advanced stage can be effectively treated, but there is also potentially immunological rejection and donor organ deficiency etc. to be asked for this method
Topic.The rise of heart tissue engineering is solves the problems, such as above-mentioned to provide new thinking.
Heart tissue engineering is the new research field to grow up in recent years, and organizational project is a combination
Molecular biology, cell biology, materialogy, the novel crossed subject of molecular mechanics, apply engineering science and life science
Principle exploitation can grow the biomaterial of gentrify damaged tissues and organ dysfunction.Its mainly include seed cell,
The content of the aspect of biologic bracket material and tissue construction etc. three.Wherein timbering material is that seed cell is grown, propagation is relied on
Adhere to support material, therefore timbering material must have certain biocompatibility, degradability, cell adhesion and with life
Good associativity between the long factor.This like cell will be adhered to differential growth on timbering material and form new tissue regions
Instead of original affected area.So the feature of timbering material can the tissue that ultimately form engineering be played it is vital
Influence.Develop for the multi-functional of heart tissue engineering（Organize generating ability and degradation property）Timbering material is current organization work
One of problem of most critical in the development of journey field.
Medical embedded hydrogel material has reliable biological safety and good biocompatibility, and it is higher aqueous
Amount is very much like with human body cell matrix environment, and the small molecule such as growth factor can freely come in and go out " cavity " inside gel.
Great number content liquid makes it suitable for cell sowing and encapsulation.Further, since its biocompatibility and excellent diffusion, it
Also highly recommended for tissue implantation and other biological medical application.And due to its can also sertoli cell adhesion and
Growth, thus hydrogel is widely used in heart tissue engineering.In recent years the medical plant of polyesters is prepared using PEG as raw material
Entering hydrogel material is prepared by adding the materials such as crosslinking agent mostly, can thus be given in gel rubber system and be introduced to organism
Harmful crosslinking agent causes cell that lesion occurs.And it is formed by curing gelation condition and can not carried out at room temperature.Such as
Hilborn, D.A.O.a. etc.（macromolecules,2006,39(5)）Hydrogel is prepared for using click-reaction, but its
Metallic catalyst and initiator are introduced in preparation process, these materials can damage to health, while in gel
Some inevitable accessory substances can be produced during change so that gel strength is greatly reduced.Yu, L et al.（Polymer
chemistry,2007,45(60)）The Thermo-sensitive water-setting of the triblock copolymer based on PEG is prepared for by in-situ injection shaping
Glue, it is leaned on.But this hydrogel mainly relies on physical action between strand（Such as, hydrogen bond）It is cross-linked to form, therefore it is handed over
Connection degree and intensity are far from enough.
Additionally due to uv-light polymerization has energy-conservation, use that is pollution-free, can avoiding cross-linking reagent, easy to operate
The advantages that, therefore often it is used to prepare medical aquogel material.But the hydrogel hardening time prepared currently with photocuring
It is longer, and and because the limitation of light penetration capacity can not be prepared, volume is larger and the uniform gel of crosslinking, while gel is consolidated
It is excessive often so that gel rubber material deformation to change shrinkage factor.So hydrogel material would not be with the life of cell after human body is implanted into
It is long to be degraded with uniform speed.Such as Sawhney（macromolecules,1993,26,58）Light-initiated it is prepared for by ultraviolet
Hydrogel based on PEG, but light gradually weakens in gel inner vertical direction intensity in the curing process, therefore can not prepare
The hydrogel material that volume is larger, crosslinking is uniform, complex-shaped.
The content of the invention
The present invention provides a kind of preparation method of the hydrogel scaffold of biological degradability for cardiac repair, to solve to pass
The problems such as immunological rejection caused by the heteroplastic transplantation method treatment heart disease of system and donor organ wretched insufficiency.
To solve the problems, such as that prior art is present, the technical scheme is that：A kind of biology drop for cardiac repair
The preparation method of the hydrogel scaffold material of solution property, it is characterised in that：The step of described preparation method is：
1）PVL-PEG-PVL preparation
A. weigh and stirred in 2g polyethylene glycol PEG and 4mL anhydrous δ-penta Inner esters addition test tube, then by polyethylene glycol
2wt%-5wt% add octoate catalyst stannous stir；
B. vacuumize 10min to reaction system and remove moisture and oxygen in reaction system, sealing system is in 110-140 DEG C of temperature
Degree lower reaction 12-16 hours；
C. the product that reaction obtains is dissolved into the bubble in dichloromethane DCM inside ultrasound removing solution, solution is moved into mould
Dichloromethane DCM is removed in tool, it is stand-by that PVL-PEG-PVL triblock copolymers are made in product；
2）It is modified
A. it is in the round-bottomed flask of the drying under the protection of nitrogen, the PVL-PEG-PVL triblock copolymers of above-mentioned synthesis is molten
Solution is cooled to 0 DEG C in anhydrous tetrahydrofuran THF, then adds the anhydrous triethylamine of 4 times of polymer, uses constant pressure addition
The tetrahydrofuran solution for the acryloyl chloride that funnel is slowly added dropwise, reactant mixture stir 4h at 0 DEG C, then mistake at room temperature
After night reaction, with 5000r/min centrifugation half an hour, triethylamine hydrochloride caused by removing, supernatant is poured out -4
The n-hexane of 5 times of excess is added at DEG C, is stood after being sufficiently stirred, outwells supernatant liquor, macromonomer is obtained, further with four
Hydrogen furans and n-hexane are good solvent and poor solvent, are dissolved, precipitation, are filtered so repeatedly twice, last 40 DEG C of vacuum drying
24h, obtains gel precursors, and lucifuge freezing is sealed；
3）Prepare hydrogel scaffold material
A. the phosphate buffer PBS that PH is 7.4 is configured
Formation concentration in phosphate buffer will be dissolved in the PVL-PEG-PVL gel precursors 0.5g of acryloyl chloride modified is
0.05g/ mL solution, being heated in magnetic agitation makes it fully dissolve；
B. the 0.5wt% of the amount in the solution obtained to above-mentioned steps a by monomer adds light trigger 2,2- dimethoxy -2- benzene
Benzoylformaldoxime DMPA, hydrogel material is formed in 5min under 365nm ultraviolet lights after stirring and dissolving is uniform.
Described step 2）The volume ratio of middle acryloyl chloride and tetrahydrofuran solution is 1:10.
The rate of addition of described constant pressure funnel is 2s/ drops.
Compared with prior art, advantages of the present invention is as follows：
Whole preparation process of the present invention has mild condition（Ultraviolet light electric current 15A）, energy-conservation, pollution-free, speed is fast（Solidification rate
In 5min）, precision it is high（Molding shrinkage 4% or so when not adding any filler）, it is easy to operate the advantages that, it is most important that
It does not have the use of toxicity crosslinking agent, biological safety height；
Hydrogel scaffold material obtained by the present invention can effectively solve heart implantation immunological rejection and donor organ is serious not
The problem of sufficient；
Hydrogel scaffold material produced by the present invention is modified by acryloyl chloride（AC）Poly- valerolactone-polyethylene glycol valerolactone
（PVL-PEG-PVL）Triblock copolymer forms；As a kind of aliphatic poly ester material except with good biocompatibility
Also there is good degradation property in addition, will not rest on for a long time in human body, and the material is that one kind can be used for UV-curing
Change 3D printing, i.e., it can use 3D printing technique to complete Individual design and customization, because material structure feature make it that it is solid
Change shrinkage factor is very low and intensity is very high, therefore printing precision is high, speed is fast, and can print multilayer aquagel as requested can meet
The demand of future clinical application.
Brief description of the drawings
Fig. 1 is synthesis PVL-PEG-PVL Fourier transform infrared spectroscopy figure；
Fig. 2 is the stress strain curve of hydrogel；
A, b are respectively the hydrogel SEM figures under different amplification in Fig. 3；
Fig. 4 is degradation curve of the hydrogel at 37 DEG C.
Embodiment
In order to make the purpose , technical scheme and advantage of the present invention be clearer, it is right below in conjunction with drawings and Examples
The present invention is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, and
It is not used in the restriction present invention.
Embodiment one：
A kind of the step of preparation method of the hydrogel scaffold material of biological degradability for cardiac repair is：
1）Poly- valerolactone-polyethylene glycol valerolactone（PVL-PEG-PVL）Preparation
A. 2g polyethylene glycol is weighed（PEG）（Water removal）With 4mL δ-penta Inner esters（δ-VL）（Water removal）Add in test tube and stir
It is even, then add 0.138g octoate catalyst stannous and stir；
B. vacuumize 10min to above-mentioned reaction system and remove moisture and oxygen in reaction system, sealing system is in 120 DEG C of temperature
The lower reaction of degree 14 hours；
C. the product that reaction obtains is dissolved into dichloromethane（DCM）Middle ultrasound removes the bubble inside solution, and solution is moved to
Dichloromethane is removed in mould（DCM）, film is made in product（PVL-PEG-PVL triblock copolymers）It is stand-by.
2）It is modified
A. in the round-bottomed flask of the drying under the protection of nitrogen, by the PVL-PEG-PVL triblock copolymers of above-mentioned synthesis
1.2g is dissolved in the anhydrous tetrahydrofurans of 20mL（THF）In, 0 DEG C is cooled to, then adds anhydrous three second of 4 times of polymer
Amine, it is slowly added dropwise with constant pressure funnel（2s/ drops）The tetrahydrofuran solution of 20mL acryloyl chlorides（Volume ratio 1：10）, reaction
Mixture stirs 4h at 0 DEG C, then at room temperature after reaction overnight, 5000r/min centrifugation half an hour, removes
Caused triethylamine hydrochloride, the n-hexane that supernatant adds 5 times of excess at -4 DEG C is poured out, stands, outwells after being sufficiently stirred
Supernatant liquor, macromonomer is obtained, further with tetrahydrofuran（THF）It is good solvent and poor solvent with n-hexane, dissolves,
Repeatedly twice, last 40 DEG C of vacuum drying 24h obtains gel precursors to suction filtration, and lucifuge freezing is sealed.
3）Prepare hydrogel scaffold material
（1）Configure the phosphate buffer that PH is 7.4（PBS）
Take acryloyl chloride（AC）The PVL-PEG-PVL gel precursors 0.5g of modified is dissolved in 10mL phosphate buffer
（PBS, PH=7.4）Middle to form the homogeneous phase solution that concentration is 0.05g/mL, being heated in magnetic agitation makes it fully dissolve；
（2）0.025g light trigger 2,2- dimethoxy -2- phenyl acetophenones are added in the solution obtained to above-mentioned steps a
（DMPA）, in ultraviolet light after stirring and dissolving is uniform（365nm）Hydrogel material is formed in lower 5min.
Embodiment 2：
A kind of the step of preparation method of the hydrogel scaffold material of biological degradability for cardiac repair is：
1）Poly- valerolactone-polyethylene glycol valerolactone（PVL-PEG-PVL）Preparation
A. 2g PEG is weighed（PEG）（Water removal）With 4mL δ-penta Inner esters（δ-VL）（Water removal）Add in test tube and stir, with
0.021g octoate catalyst stannous is added afterwards to stir；
B. vacuumize 10min to reaction system and remove moisture and oxygen in reaction system, sealing system is at a temperature of 130 DEG C
Reaction 15 hours；
C. the product that reaction obtains is dissolved into dichloromethane（DCM）Middle ultrasound removes the bubble inside solution, and solution is moved to
Dichloromethane is removed in mould（DCM）, film is made in product（PVL-PEG-PVL triblock copolymers）It is stand-by.
2）It is modified
A. in the round-bottomed flask of the drying under the protection of nitrogen, by the PVL-PEG-PVL triblock copolymers of above-mentioned synthesis
1.2g is dissolved in the anhydrous tetrahydrofurans of 20mL（THF）In, 0 DEG C is cooled to, then adds anhydrous three second of 4 times of polymer
Amine, it is slowly added dropwise with constant pressure funnel（2s/ drops）The tetrahydrofuran solution of 20mL acryloyl chlorides（Volume ratio 1：10）, reaction
Mixture stirs 4h at 0 DEG C, is then centrifuged at room temperature after reaction overnight（5000r/min）Half an hour, remove and produce
Triethylamine hydrochloride, pour out supernatant add 5 times of excess n-hexane（-4℃）, stood after being sufficiently stirred, it is clear to outwell upper strata
Liquid, macromonomer is obtained, further with tetrahydrofuran（THF）It is good solvent and poor solvent with n-hexane, dissolve, precipitate,
Filter, repeatedly twice, dry 24h in 40 DEG C very lower, lucifuge freezing is sealed, and obtains gel precursors.
3）Prepare hydrogel scaffold material
（1）Configure the phosphate buffer that PH is 7.4（PBS）.
Acryloyl chloride will be used（AC）The PVL-PEG-PVL gel precursors 0.5g of modified is dissolved in 10mL phosphate buffer
（PBS, PH=7.4）Middle to form the homogeneous phase solution that concentration is 0.05g/ mL, being heated in magnetic agitation makes it fully dissolve；
（2）0.025g light trigger 2,2- dimethoxy -2- phenyl acetophenones are added in the solution obtained to above-mentioned steps a
（DMPA）, in ultraviolet light after stirring and dissolving is uniform（365nm）Hydrogel material is formed in lower 5min.
With embodiment 2 it is most preferred embodiment in above example, the result tested it is as follows：
Step 1）Selected in PEG hydrogels have good biocompatibility, will not produce immunological rejection after human body is implanted into
Reaction, but the inertia on its surface make it that the adhesion property of cell and growth factor is very poor.And with δ-penta Inner esters（δ-VL）And PEG
Certain cell adhesiveness can be provided for it by reacting obtained block copolymer PVL-PEG-PVL copolymers, improve its degraded speed
Rate and mechanical strength.
As can be seen from Figure 1 absworption peak caused by the scissoring vibration of δ-VL 1395cm-1 hexatomic ring is originally belonged to
With hexatomic ring conjugation at 1466cm-1 caused by absworption peak disappeared, it was demonstrated that δ-VL ring-opening polymerisations, pass through contrast it is single
The infrared spectrogram of body and synthetic segmented copolymer, and the vibrational band special to these is analyzed, and as a result proves PVL-
PEG-PVL block copolymers successfully synthesize；
Step 2）It is middle modified with AC after its there is certain light-cured performance, solidification rate is fast（In 5min）And when printing layer by layer
There is enough intensity to keep its shape not cave in, sufficiently long strand cause its solidification process in gel shrinkage factor very
Its low i.e. printing precision is very high.Therefore it is especially suitable for quick 3D printing and prepares hydrogel scaffold for cardiac tissue repair.
Step 3）Gel precursors solution viscosity 1-300mPa/s, the tensile strength of the timbering material of middle preparation are not less than
50KPa, modulus are not less than 22.7KPa.
As can be seen from Figure 2 the modulus of the hydrogel（E）For 56KPa, intensity 332KPa, strain are 358.791 %,
（Natural cardiac muscular tissue modulus is 22.7Kpa, intensity 50Kpa, strains 15-22%）；
Fig. 3 shows the cross-linked structure of gel internal porous and can show inside hydrogel that the degree of cross linking is very between macromolecular chain
Height, network-intensive；
The overall degradation rate of gel is than more uniform as can be seen from Figure 4, and can is degraded to original quality in 14 days
93.2%。
The foregoing is only a preferred embodiment of the present invention, is not intended to limit the scope of the present invention.
Claims (3)
- A kind of 1. preparation method of the hydrogel scaffold material of biological degradability for cardiac repair, it is characterised in that：It is described Preparation method the step of be：1）PVL-PEG-PVL preparationA. weigh and stirred in 2g polyethylene glycol PEG and 4mL anhydrous δ-penta Inner esters addition test tube, then by polyethylene glycol 2wt%-5wt% add octoate catalyst stannous stir；B. vacuumize 10min to reaction system and remove moisture and oxygen in reaction system, sealing system is in 110-140 DEG C of temperature Degree lower reaction 12-16 hours；C. the product that reaction obtains is dissolved into the bubble in dichloromethane DCM inside ultrasound removing solution, solution is moved into mould Dichloromethane DCM is removed in tool, it is stand-by that PVL-PEG-PVL triblock copolymers are made in product；2）It is modifiedA. it is in the round-bottomed flask of the drying under the protection of nitrogen, the PVL-PEG-PVL triblock copolymers of above-mentioned synthesis is molten Solution is cooled to 0 DEG C in anhydrous tetrahydrofuran THF, then adds the anhydrous triethylamine of 4 times of polymer, uses constant pressure addition The tetrahydrofuran solution for the acryloyl chloride that funnel is slowly added dropwise, reactant mixture stir 4h at 0 DEG C, then mistake at room temperature After night reaction, with 5000r/min centrifugation half an hour, triethylamine hydrochloride caused by removing, supernatant is poured out -4 The n-hexane of 5 times of excess is added at DEG C, is stood after being sufficiently stirred, outwells supernatant liquor, macromonomer is obtained, further with four Hydrogen furans and n-hexane are good solvent and poor solvent, are dissolved, precipitation, are filtered so repeatedly twice, last 40 DEG C of vacuum drying 24h, obtains gel precursors, and lucifuge freezing is sealed；3）Prepare hydrogel scaffold materialA. the phosphate buffer PBS that PH is 7.4 is configuredFormation concentration in phosphate buffer will be dissolved in the PVL-PEG-PVL gel precursors 0.5g of acryloyl chloride modified is 0.05g/ mL solution, being heated in magnetic agitation makes it fully dissolve；B. the 0.5wt% of the amount in the solution obtained to above-mentioned steps a by monomer adds light trigger 2,2- dimethoxy -2- benzene Benzoylformaldoxime DMPA, hydrogel material is formed in 5min under 365nm ultraviolet lights after stirring and dissolving is uniform.
- 2. the preparation method of the hydrogel scaffold material of the biological degradability according to claim 1 for cardiac repair, It is characterized in that：Described step 2）The volume ratio of middle acryloyl chloride and tetrahydrofuran solution is 1:10.
- 3. the preparation side of the hydrogel scaffold material of the biological degradability according to claim 1 or 2 for cardiac repair Method, it is characterised in that：The rate of addition of described constant pressure funnel is 2s/ drops.
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