CN115558133A - Temperature response type particle gel and preparation method thereof - Google Patents
Temperature response type particle gel and preparation method thereof Download PDFInfo
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- CN115558133A CN115558133A CN202211284951.7A CN202211284951A CN115558133A CN 115558133 A CN115558133 A CN 115558133A CN 202211284951 A CN202211284951 A CN 202211284951A CN 115558133 A CN115558133 A CN 115558133A
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- 238000000034 method Methods 0.000 claims abstract description 12
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- 238000006116 polymerization reaction Methods 0.000 claims abstract description 5
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- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 claims description 10
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 8
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- 238000007334 copolymerization reaction Methods 0.000 claims description 4
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- GJKGAPPUXSSCFI-UHFFFAOYSA-N 2-Hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone Chemical group CC(C)(O)C(=O)C1=CC=C(OCCO)C=C1 GJKGAPPUXSSCFI-UHFFFAOYSA-N 0.000 claims description 2
- DBCAQXHNJOFNGC-UHFFFAOYSA-N 4-bromo-1,1,1-trifluorobutane Chemical compound FC(F)(F)CCCBr DBCAQXHNJOFNGC-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 2
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- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 claims description 2
- 229920005650 polypropylene glycol diacrylate Polymers 0.000 claims description 2
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 2
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 2
- 239000008158 vegetable oil Substances 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 2
- 238000005191 phase separation Methods 0.000 abstract description 6
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- OZAIFHULBGXAKX-UHFFFAOYSA-N 2,2'-azo-bis-isobutyronitrile Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 description 4
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- 229920013731 Dowsil Polymers 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
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- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 238000012711 chain transfer polymerization Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- 238000006062 fragmentation reaction Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- ZIUHHBKFKCYYJD-UHFFFAOYSA-N n,n'-methylenebisacrylamide Chemical compound C=CC(=O)NCNC(=O)C=C ZIUHHBKFKCYYJD-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
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- LSWCMUBJZBXTDM-UHFFFAOYSA-M P(=O)(OC1=CC=CC=C1)(OC(C1=C(C=C(C=C1C)C)C)=O)[O-].[Li+] Chemical compound P(=O)(OC1=CC=CC=C1)(OC(C1=C(C=C(C=C1C)C)C)=O)[O-].[Li+] LSWCMUBJZBXTDM-UHFFFAOYSA-M 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 238000010560 atom transfer radical polymerization reaction Methods 0.000 description 1
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- 230000007423 decrease Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000007863 gel particle Substances 0.000 description 1
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- 238000011534 incubation Methods 0.000 description 1
- 239000000976 ink Substances 0.000 description 1
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- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229920013730 reactive polymer Polymers 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- 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
-
- 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
- C08J2351/00—Characterised by the use of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives of such polymers
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- Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Colloid Chemistry (AREA)
Abstract
The invention discloses a temperature response type particle gel and a preparation method thereof, wherein the particle gel comprises a hydrophilic shell layer and a temperature-sensitive core layer, the hydrophilic shell layer is a branched polyvinyl macromolecule, and the temperature-sensitive core layer is a temperature-sensitive polymer; the preparation method comprises the following steps: (1) Dissolving branched polyvinyl macromolecule, temperature-sensitive polymer monomer or low molecular weight polymer and initiator in water to obtain water phase; (2) Dispersing the water phase in an oil phase to prepare W/O water-in-oil droplets; (3) Initiating the W/O water-in-oil droplets to carry out polymerization reaction by heating, irradiation or redox reaction to obtain hydrogel particles; (4) And concentrating and dispersing the prepared hydrogel particles into deionized water to obtain the temperature response type particle gel. The hydrophilic shell layer is wrapped outside the temperature-sensitive core layer, the fluidity of the particle gel is improved along with the rise of the temperature and weakened along with the reduction of the temperature, and the problems of phase separation and blockage in the printing process caused by over-strong hydrophobic effect of the traditional temperature-sensitive particles are effectively solved.
Description
Technical Field
The invention relates to a biological particle gel and a preparation method thereof, in particular to a temperature response type particle gel and a preparation method thereof.
Background
Particle gels refer to a class of viscoelastic materials composed of micron-sized hydrogel particles. Compared with the traditional hydrogel block material, the particle gel has the basic characteristics of high water content and good biocompatibility, and also has the unique advantages of shear thinning, high specific surface area, large porosity, injectability and the like. The volume fraction of hydrogel particles in the particulate gel material exceeds 58%, and therefore, close contact between hydrogel particles and a physical blocking (Jamming) effect occur. This Jamming effect causes the particulate gel to assume a solid form when subjected to relatively small external shear forces; when the external force exceeds a certain threshold value, the hydrogel particles slide to each other, and the flow characteristics begin to appear. Based on the principle, a series of particle gel bio-inks are developed successively and applied to the fields of tissue engineering and biomedicine.
The forces between hydrogel particles in the particle gel have a significant influence on the stability of the bioprinting process. When the acting force between the particles is too large, the extrusion resistance of the particles is greatly increased, and the filaments cannot be produced; when the particle-to-particle force is too low, the particle gel modulus is too low, resulting in collapse or distortion of the printed structure. To solve this problem, researchers have proposed a printing-followed "welding" strategy, for example, by introducing microsphere "binders" such as reactive polymers, metal ions, etc. into the printed structure, and further "crosslinking" the microsphere particles to improve the mechanical properties of the printed product. In recent years, researchers have also attempted to adjust the rheological properties of particulate gels by introducing temperature sensitive materials (angelw. Chem. Int. Ed.2022,61, 202114602). The temperature-sensitive particles can reduce the volume at high temperature so as to reduce the volume fraction of the temperature-sensitive particles in the particle gel, so that the friction effect can be effectively weakened theoretically, and the fluidity of the particle gel is improved; however, hydrophobic interaction between particles is increased due to the hydrophobic nature of the particles at high temperatures, and phase separation may even occur in the extreme. Therefore, the two completely opposite effects cause the rheological property of the particle gel to be complex along with the temperature change rule, and the actual printing process cannot be effectively matched.
Disclosure of Invention
The invention aims to: the invention aims to provide a temperature-responsive granular gel which has the characteristic of pure positive temperature sensitivity, improves the fluidity along with the rise of temperature and effectively avoids the problem that printing nozzles are blocked due to hydrophobic-hydrophobic interaction force or phase splitting generated between traditional temperature-sensitive hydrogel granules at high temperature; the second purpose of the invention is to provide a preparation method of the temperature response type particle gel.
The technical scheme is as follows: the temperature response type particle gel comprises a hydrophilic shell layer and a temperature-sensitive core layer, wherein the hydrophilic shell layer is a branched polyvinyl macromolecule; the temperature-sensitive core layer is a temperature-sensitive polymer.
Preferably, the branched polyvinyl macromolecule is obtained by copolymerization of ethylene glycol type polyvinyl monomer or low molecular weight polymer, wherein the ethylene glycol type polyvinyl monomer or low molecular weight polymer is one or more of ethylene glycol dimethacrylate, ethylene glycol diacrylate, polyethylene glycol diacrylate, polypropylene glycol diacrylate and polyethylene glycol dimethacrylate. The molecular weight of the branched polyvinyl macromolecule is 10 kDa-30 kDa.
The polymerization reaction is atom transfer radical polymerization, reversible addition/fragmentation chain transfer polymerization or chain transfer termination polymerization. Reversible addition/fragmentation chain transfer polymerization is preferred.
Preferably, the temperature-sensitive polymer is obtained by copolymerization of a monomer or a low-molecular weight polymer, and the monomer or the low-molecular weight polymer is at least one of isopropyl acrylamide, polyether F127 dipropyl acrylate, maleimide-terminated poly (N-isopropyl acrylamide) and N-hydroxysuccinimide ester-terminated poly (N-isopropyl acrylamide).
Preferably, the average particle diameter of the constituent unit of the particulate gel is 5 to 300. Mu.m.
The preparation method of the temperature response type particle gel comprises the following steps:
(1) Dissolving branched polyvinyl macromolecule, temperature-sensitive polymer monomer or low molecular weight polymer and initiator in water to obtain water phase;
(2) Dispersing the water phase in an oil phase to prepare W/O water-in-oil droplets;
(3) Initiating the W/O water-in-oil droplets to carry out polymerization reaction by heating, irradiation or redox reaction to obtain hydrogel particles;
(4) And concentrating and dispersing the prepared hydrogel particles into deionized water to obtain the temperature response type particle gel.
Preferably, the initiator is a photoinitiator, a thermal initiator or a redox initiator, and the photoinitiator is 2-hydroxy-4' - (2-hydroxyethoxy) -2-methyl propiophenone or lithium phenyl (2, 4, 6-trimethylbenzoyl) phosphate; the thermal initiator is azodiisobutyramidine hydrochloride, ammonium persulfate, potassium persulfate or sodium persulfate; the redox initiator is composed of persulfate and tetramethylethylenediamine.
Preferably, the oil phase comprises one of vegetable oil, mineral oil, fluorinated oil and silicone oil.
Preferably, the W/O water-in-oil droplet is prepared by a micro-fluidic method, a membrane emulsification method or a mechanical stirring method.
Preferably, the volume fraction of hydrogel particles in the particulate gel is 58% to 100%.
The invention mechanism is as follows: the particle gel is obtained by copolymerizing W/O water-in-oil droplets serving as a template and a branched polyvinyl macromolecule and a polymer monomer or a low-molecular-weight polymer with a temperature-sensitive characteristic serving as main raw materials. Because the branched polyvinyl macromolecules have amphiphilicity, the branched polyvinyl macromolecules can be enriched on the surface of the W/O water-in-oil droplet, so that the particle gel with the hydrophilic shell layer and the temperature-sensitive core layer structure is formed. Due to the structural characteristics of the hydrophilic shell layer and the temperature-sensitive core layer, the particle gel is subjected to volume shrinkage at the temperature higher than the critical phase transformation temperature of the core layer, the volume fraction of the particle gel is reduced, and the inter-particle blocking (Jamming) effect is weakened; meanwhile, the hydrophilic shell of the particle gel effectively avoids hydrophobic-hydrophobic interaction between particles. Therefore, the fluidity of the particle gel is improved along with the temperature rise and is weakened along with the temperature fall, and the phase separation of the traditional temperature-sensitive particles caused by the over-strong hydrophobic effect is effectively avoided. In addition, since the branched polyvinyl macromolecules on the surface of the particle gel contain a large number of active double bonds, modification and modification can be conveniently carried out through a Michael addition reaction and the like.
Has the advantages that: compared with the prior art, the invention has the following remarkable advantages: (1) The particle gel wraps the hydrophilic shell layer outside the temperature-sensitive core layer, the fluidity of the particle gel is improved along with the rise of temperature, and is weakened along with the reduction of temperature, so that the problems of phase separation and blockage in the printing process caused by over-strong hydrophobic effect of the traditional temperature-sensitive particles are effectively solved; (2) The branched polyvinyl macromolecules on the surface of the particle gel contain a large number of active double bonds, are easy to modify, are convenient for modifying various proteins or medicines, and have important value in the field of tissue engineering or medicine delivery.
Drawings
FIG. 1 is a schematic diagram of the preparation of a temperature responsive particulate gel of the present invention;
FIG. 2 is a chemical structure and nuclear magnetic hydrogen spectrum of the branched polyvinyl macromolecule prepared in example 1 of the present invention;
FIG. 3 is a chemical formula and nuclear magnetic hydrogen spectrum of polyether F127 dipropyl acrylate in example 3;
FIG. 4 is a microscopic image of the granular gel prepared in example 1 under different temperature conditions;
FIG. 5 is a graph of the macroscopic physical state of the particulate gel prepared in example 1 under different temperature conditions;
FIG. 6 is a microscopic image of the granular gel prepared in example 3 under different temperature conditions;
FIG. 7 is a diagram of the macroscopic physical state of the particulate gel prepared in example 3 under different temperature conditions;
FIG. 8 is a graph showing the effect of hydrophobic-hydrophobic interaction force at 45 ℃ of the microgel particles prepared in example 1;
FIG. 9 is a graph showing the effect of hydrophobic-hydrophobic interaction at 45 ℃ of the particulate gel prepared in example 1;
FIG. 10 is a pictorial view of a particulate gel extrusion and biological stent made in example 2 of the present invention;
fig. 11 is a fluorescence map and a fluorescence intensity map before and after the reaction of the microgel prepared in example 1 of the present invention with thiolated rhodamine.
Detailed Description
The technical solution of the present invention is further illustrated by the following examples.
Example 1
The preparation method of the temperature response type particle gel comprises the following steps:
(1) Preparation of branched polyvinyl macromolecule (HB-PEGDA)
13.625g of poly (ethylene glycol) diacrylate (PEGDA) monomer was charged into a 250mL three-necked flask, and 62.5mL of butanone solution were added, and the magnetic stirrer was turned on at 300rpm until complete dissolution. Then, 0.296g of tetraethylthiuram Disulfide (DS), 0.295g of 2, 2-Azobisisobutyronitrile (AIBN) were further added. Argon gas was bubbled for 1h. After the oxygen discharge is finished, the solution in the three-neck flask reacts for 10 hours at 70 ℃, and then air is introduced to terminate the reaction.
The synthesized branched polyvinyl macromolecular structure and nuclear magnetism result are shown in figure 1. 1H NMR (400MHz, deuterium Oxide). Delta.4.34-4.28 (m, 1H), 4.25 (s, 1H), 4.13 (s, 8H), 3.82-3.75 (m, 1H), 3.70-3.63 (m, 10H), 1.73 (s, 1H).
(2) Precursor liquid preparation
60mg of ammonium persulfate (NH) 4 ) 2 S 2 O 8 120mg of branched polyvinyl macromolecule (HB-PEGDA) was dissolved in 2mL of 1 XPBS having pH =7.4, and was prepared as dispersed phase A1 having a concentration of 6% (w/v); 280mg of N-isopropylacrylamide (NIPAAm) was dissolved in 2mL of 1 XPBS at pH =7.4, and 20. Mu.L of Tetramethylethylenediamine (TEMED) was added to prepare a dispersion phase A2 having a concentration of 14% (w/v).
(3) Preparation of temperature-responsive particulate gel
And dissolving a surfactant (FE-surf) in the fluorine oil to prepare a continuous phase B1 (oil phase) with the mass fraction of 2%. Respectively connecting the solutions A1 and A2 prepared in the step (2) with a microfluidic chip through pipelines; and adjusting the flow rate of the oil phase B1 to be 40 mu L/min, the flow rate of the water phase A1 to be 4 mu L/min and the flow rate of the water phase A2 to be 4 mu L/min, preparing monodisperse droplets through a microfluidic chip, waiting for 1h for a free radical reaction to solidify the droplets to form hydrogel particles, washing out the hydrogel particles, concentrating and dispersing the hydrogel particles in deionized water to obtain particle gel with the particle size distribution of 150-170 mu m (as shown in figure 4 a).
Example 2
The preparation method of the temperature response type particle gel comprises the following steps:
(1) The branched polyvinyl macromolecule (HB-PEGDA) was prepared as in example 1.
(2) Precursor liquid preparation
10mg of lithium phenyl (2, 4, 6-trimethylbenzoyl) phosphate salt and 100mg of branched polyvinyl macromolecule (HB-PEGDA) were dissolved in 1mL of 1 XPBS at pH =7.4 to prepare a dispersion phase A1 having a concentration of 10% (w/v); 280mg of N-isopropylacrylamide (NIPAAm) was dissolved in 2mL of 1 × PBS at pH =7.4 to prepare a dispersed phase A2 with a concentration of 14% (w/v).
(3) Preparation of temperature-responsive particulate gel
A surfactant (DOWSIL RSN-0749) is dissolved in the dimethyl silicone oil to prepare a continuous phase B1 (oil phase) with the mass fraction of 5%. Respectively connecting the solutions A1 and A2 prepared in the step (2) with a microfluidic chip through pipelines; and adjusting the flow rate of the oil phase B1 to be 30 mu L/min, the flow rate of the water phase A1 to be 2 mu L/min and the flow rate of the water phase A2 to be 2 mu L/min, preparing monodisperse droplets through a microfluidic chip, irradiating the droplets for 30min through blue light to solidify the droplets to form hydrogel particles, washing out the hydrogel particles, concentrating and dispersing the hydrogel particles in deionized water to obtain particle gel with the particle size distribution of 150-170 mu m.
Example 3
The preparation method of the temperature response type particle gel comprises the following steps:
(1) The branched polyvinyl macromolecule (HB-PEGDA) was prepared as in example 1.
(2) Preparation of precursor solution
120mg of branched polyvinyl macromolecule (HB-PEGDA) was dissolved in 2mL of 1 XPBS having pH =7.4 to prepare a dispersed phase A1 having a concentration of 6% (w/v), and 60mg of ammonium persulfate ((NH-GDA) was added 4 ) 2 S 2 O 8 ) (ii) a 280mg of F127-DA) was dissolved in 2mL of 1 XPBS at pH =7.4 and added20 μ L of Tetramethylethylenediamine (TEMED) configured to a concentration of 14% (w/v) dispersed phase A2;
the nuclear magnetic diagram of F127-DA is shown in FIG. 3, 1H NMR (400MHz, deuterium Oxide) delta 3.63 (s, 34H), 3.59-3.46 (m, 3H), 3.39 (ddt, J =10.4,5.1,2.7Hz, 2H), 3.09 (qd, J =7.3,4.8Hz, 1H), 1.40 (t, J =7.3Hz, 2H), 1.25 (s, 2H), 1.23 (t, J =7.0Hz, 1H), 1.12 (dd, J =6.1,3.3Hz, 8H). The presence of double bonds was confirmed by the presence of a peak at chemical shifts 5-7, which was identified as a chemical shift of the olefin, as seen in the nuclear magnetic spectrum.
(3) Preparation of temperature-responsive particulate gel
A surfactant (DOWSIL RSN-0749) is dissolved in the dimethyl silicone oil to prepare a continuous phase B1 (oil phase) with the mass fraction of 5%. Respectively connecting the solutions A1 and A2 prepared in the step (2) with a microfluidic chip through pipelines; and adjusting the flow rate of the oil phase B1 to be 40 mu L/min, the flow rate of the water phase A1 to be 4 mu L/min and the flow rate of the water phase A2 to be 4 mu L/min, preparing monodisperse liquid drops, curing for 1h to form hydrogel particles, washing out the hydrogel particles and dispersing the hydrogel particles in deionized water to obtain particle gel with the particle size distribution of 150-170 mu m. As shown in fig. 6.
Example 4
The preparation method of the temperature response type particle gel comprises the following steps:
(1) Preparation of branched polyvinyl Large molecule (HB-EGDMA)
4.955g of polyethylene glycol diacrylate (EGDMA) are introduced into a 250mL three-necked flask, 62.5mL of butanone solution are added, and the magnetic stirrer is switched on until complete dissolution is achieved at 300 rpm. Then, 0.296g of tetraethylthiuram Disulfide (DS), 0.295g of 2, 2-Azobisisobutyronitrile (AIBN) were added in this order to the flask. Argon was bubbled for 1h. After the oxygen discharge is finished, the solution in the three-neck flask reacts for 10 hours at 70 ℃, and then air is introduced to stop the reaction.
(2) Precursor liquid preparation
60mg of ammonium persulfate (NH 4) 2 S 2 O 8 120mg of branched polyvinyl macromolecule (HB-EGDMA) was dissolved in 2mL of 1 XPBS with pH =7.4, and dispersed phase A1 was prepared at a concentration of 6% (w/v); 20 μ L of Tetramethylethylenediamine (TEMED) and 280mg of N-isopropylpropaneEnamides (NIPAAm) were dissolved in 2mL 1 × PBS at pH =7.4 and formulated into 14% (w/v) dispersed phase A2.
(3) Preparation of temperature response type particle gel
And (3) dissolving a fluorinated surfactant (FE-surf) in the fluorine oil to prepare a continuous phase B1 (oil phase) with the mass fraction of 2%. Respectively connecting the prepared solutions A1 and A2 with a microfluidic chip through pipelines; and adjusting the flow rate of the oil phase B1 to be 40 mu L/min, the flow rate of the water phase A1 to be 4 mu L/min and the flow rate of the water phase A2 to be 4 mu L/min, preparing monodisperse droplets through a microfluidic chip, waiting for 1h for a free radical reaction to solidify the droplets to form hydrogel particles, washing out the hydrogel particles and dispersing the hydrogel particles in deionized water to obtain particle gel with the particle size distribution of 150-170 mu m.
Comparative example 1
1. Preparation of particle gel consisting of poly N-isopropyl acrylamide hydrogel microspheres
The branched polyvinyl macromolecule was replaced with the crosslinker N, N' -Methylenebisacrylamide (MBA) on the basis of example 1.
Characterization of Properties
(1) Testing temperature-sensitive characteristic of particle gel
The granular gels having a volume fraction of 58% prepared in examples 1 and 3 were placed at 25 ℃ and 45 ℃, respectively, and the change in particle size of the gel particles was observed under a microscope, and then the state of the gel was observed by centrifugation so that the volume fraction of the gel was 70%, as shown in fig. 4 to 7.
As can be seen from FIG. 4, the hydrogel particles prepared in example 1 shrunk in particle size by about 10% at 45 ℃. The macroscopic physical state of the particle gel at 25 ℃ and 45 ℃ is shown in FIG. 5, which further demonstrates that the hydrogel particle size decreases at elevated temperatures.
As can be seen from FIG. 6, the particle size of the hydrogel particles prepared in example 3 shrunk by about 10% at 45 ℃. The macroscopic physical state of the particle gel at 25 ℃ and 45 ℃ is further demonstrated by the reduction in particle size of the hydrogel particles at elevated temperatures, as shown in FIG. 7.
(2) Particle gel hydrophobic-hydrophobic force effect test
The particle gels prepared in example 1 and comparative example 1 with a volume fraction of 58% were placed at 45 ℃ and the hydrophobic-hydrophobic force results of the particle gels are shown in figures 8 and 9.
As can be seen from fig. 8, the phase separation of the particulate gel formed of the poly N-isopropylacrylamide hydrogel microspheres synthesized in comparative example 1 occurred greatly due to the hydrophobic-hydrophobic interaction at 45 ℃.
As can be seen from fig. 9, when the hydrogel particles with hydrophilic shells prepared in example 1 are subjected to a particle gel temperature of 45 ℃, the hydrogel particles can still be well dispersed due to the presence of the hydrophilic shells, and the occurrence of phase separation is effectively suppressed.
(3) Bio-printing
Centrifuging the granular gel with the volume fraction of 58% in example 2 to obtain granular gel with the volume fraction of 70%, and printing by using an extrusion type bioprinter at the printing speed of 400mm/min under the extrusion pressure of 20psi; the granular gel of example 2 was then filled into a cartridge and the temperature of the cartridge was raised and extruded through a 21G needle to construct a biological scaffold. As shown in fig. 10, the granulated gel prepared by the present embodiment can be smoothly and continuously extruded by an extrusion type 3D printer, and at the same time, a biological stent can be constructed.
(4) Testing of double bonds on the surface of the particle gel
Dissolving 2mg of SH-PEG-Rhodamine in 1mL of PBS, and marking as a water solution B; 1mL of PBS was used as a control, and the pH was adjusted to 7.4, which was recorded as aqueous solution A. 100mg of the particle gel prepared in example 1 was placed in the above aqueous solutions (A, B), and incubated for 20min. After the incubation, excess SH-PEG-Rhodamine solution was washed away with PBS and observed with a fluorescence microscope, the results are shown in FIG. 11.
As shown in fig. 11, the surface of the particle gel in the solution a has fluorescence, which indicates that SH-PEG-Rhodamine is successfully grafted on the surface of the particle gel, indicating that the surface of the particle gel contains a large amount of active double bonds, thereby facilitating the subsequent functional modification application.
Claims (9)
1. The temperature-responsive particle gel is characterized by comprising a hydrophilic shell layer and a temperature-sensitive core layer, wherein the hydrophilic shell layer is a branched polyvinyl macromolecule, and the temperature-sensitive core layer is a temperature-sensitive polymer.
2. The temperature-responsive particulated gel according to claim 1, wherein said branched polyvinyl macromolecule is obtained by copolymerization of a glycol-based polyvinyl monomer or low molecular weight polymer, said glycol-based polyvinyl monomer or low molecular weight polymer being one or more of ethylene glycol dimethacrylate, ethylene glycol diacrylate, polyethylene glycol diacrylate, polypropylene glycol diacrylate and polyethylene glycol dimethacrylate.
3. The temperature-responsive particulate gel of claim 1, wherein the temperature-sensitive polymer is obtained by copolymerization of a monomer or low molecular weight polymer, the monomer or low molecular weight polymer being at least one of isopropylacrylamide, polyether F127 dipropylecrylate, maleimide-terminated poly (N-isopropylacrylamide), N-hydroxysuccinimide ester-terminated poly (N-isopropylacrylamide).
4. The temperature-responsive particulate gel according to claim 1, wherein the average particle diameter of the constituent unit of the particulate gel is 5 to 300 μm.
5. A method of preparing a temperature responsive particulate gel as claimed in any one of claims 1 to 4, comprising the steps of:
(1) Dissolving branched polyvinyl macromolecule, temperature-sensitive polymer monomer or low molecular weight polymer and initiator in water to obtain water phase;
(2) Dispersing the water phase in an oil phase to prepare W/O water-in-oil droplets;
(3) Initiating the W/O water-in-oil droplets to carry out polymerization reaction by heating, irradiation or redox reaction to obtain hydrogel particles;
(4) And concentrating and dispersing the prepared hydrogel particles into deionized water to obtain the temperature response type particle gel.
6. The method of claim 5, wherein the initiator is a photoinitiator, a thermal initiator, or a redox initiator, and the photoinitiator is 2-hydroxy-4' - (2-hydroxyethoxy) -2-methylpropiophenone or lithium phenyl (2, 4, 6-trimethylbenzoyl) phosphate; the thermal initiator is azodiisobutyramidine hydrochloride, ammonium persulfate, potassium persulfate or sodium persulfate; the redox initiator is composed of persulfate and tetramethyl ethylenediamine.
7. The method of claim 5, wherein the oil phase comprises one of vegetable oil, mineral oil, fluorinated oil, and silicone oil.
8. The method for preparing temperature-responsive particle gel according to claim 5, wherein the W/O water-in-oil droplet is prepared by microfluidics, membrane emulsification or mechanical stirring.
9. The method of claim 5, wherein the volume fraction of hydrogel particles in the particulate gel is between 58% and 100%.
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