CN118440361A - Particle gel with uniformly distributed pores and preparation method and application thereof - Google Patents
Particle gel with uniformly distributed pores and preparation method and application thereof Download PDFInfo
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- CN118440361A CN118440361A CN202410555016.2A CN202410555016A CN118440361A CN 118440361 A CN118440361 A CN 118440361A CN 202410555016 A CN202410555016 A CN 202410555016A CN 118440361 A CN118440361 A CN 118440361A
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 31
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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
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
- C08J3/246—Intercrosslinking of at least two polymers
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F299/00—Macromolecular compounds obtained by interreacting polymers involving only carbon-to-carbon unsaturated bond reactions, in the absence of non-macromolecular monomers
- C08F299/02—Macromolecular compounds obtained by interreacting polymers involving only carbon-to-carbon unsaturated bond reactions, in the absence of non-macromolecular monomers from unsaturated polycondensates
- C08F299/026—Macromolecular compounds obtained by interreacting polymers involving only carbon-to-carbon unsaturated bond reactions, in the absence of non-macromolecular monomers from unsaturated polycondensates from the reaction products of polyepoxides and unsaturated monocarboxylic acids, their anhydrides, halogenides or esters with low molecular weight
-
- 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
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- 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
- C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
- C08J2405/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- 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
- C08J2455/00—Characterised by the use of homopolymers or copolymers, obtained by polymerisation reactions only involving carbon-to-carbon unsaturated bonds, not provided for in groups C08J2423/00 - C08J2453/00
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
Abstract
The invention discloses a particle gel with uniformly distributed pores, and a preparation method and application thereof. The particle gel consists of high molecular particles with surface modified sulfhydryl groups and a polyvinyl polymer cross-linking agent; and (3) carrying out crosslinking reaction on the dispersion liquid of the high molecular particles with the surface modified sulfhydryl groups and a polyvinyl polymer crosslinking agent to prepare the particle gel. The cross-linking agent among particles of the particle gel obtained by the method can not spontaneously gel to form gel blocks, so that pores among the particles of the particle gel are blocked, the pores are uniformly distributed, the preparation condition of the particle gel is mild, and the biological performance is obviously improved.
Description
Technical Field
The invention relates to the technical field of hydrogel particles, in particular to a particle gel with uniformly distributed pores, and a preparation method and application thereof.
Background
Particle gel is a viscoelastic hydrogel material composed of high-density stacked tiny particles, and has the unique advantages of injectability, self-healing, macroporous characteristics and the like. The material has wide application prospect in the fields of biological printing, regenerative medicine, drug delivery and the like. Its injectability allows for flexibility in medical applications to be injected into the target area, while its self-healing nature allows for reconnection after injury, preserving structural integrity. The macroporous characteristic of the particle gel has positive effects on the aspects of cell growth, medicine diffusion and the like, and provides powerful support for innovative medical treatment and material research. The sintering of the particle gel is to crosslink gel particles by physical or chemical methods to form a massive macroporous bracket.
The sintered particle gel or the crosslinked particle gel is a material which further strengthens the interaction between particles in the particle gel by physical or chemical action, thereby being beneficial to greatly improving the mechanical properties of the particle gel material. This type of particulate gel exhibits excellent structural fidelity and good integration into host tissue in tissue engineering scaffold applications.
At present, the enhancement of the action of the gel particle units can be achieved in various ways, including chemical covalent crosslinking, metal ion complexation, hydrophilic-hydrophobic action, enzymatic reaction and the like. Compared with reversible crosslinking or physical crosslinking, chemical covalent crosslinking has the advantage of more stable and durable structure, and becomes an important direction of research. However, conventional crosslinking processes often require harsh conditions, such as ultraviolet radiation, photocrosslinkers or organic chemical crosslinkers, which can lead to deactivation of the active ingredient in the particle gel. In recent years, covalent attachment between gel particles has been implemented by introducing "bridging" components into the particulate gel system, a popular particulate gel sintering strategy. However, such introduced components still require the above-mentioned harsh reaction conditions, and self-crosslinking of the "bridging component" may also occur during particle crosslinking, forming local hydrogel blocks, blocking the intrinsic interpenetrating macroporous network of the particle gel, sacrificing the differences in pore characteristics between batches of particle gel, resulting in a reduction in the biological properties of the particle gel.
Disclosure of Invention
The invention aims to provide a preparation method of particle gel with uniformly distributed pores. Gel blocks are not formed among particles of the particle gel obtained by the preparation method, pores among the particles of the particle gel are not blocked, the pores are uniformly distributed, the preparation condition of the particle gel is mild, and the biological performance is obviously improved.
In order to achieve the above purpose, the invention adopts the following technical scheme:
A method of preparing a particulate gel, the method comprising the steps of: carrying out cross-linking reaction on dispersion liquid of particles with surface modified sulfhydryl groups and a cross-linking agent to prepare the particle gel; the cross-linking agent is a polyvinyl polymer; the surface-modified sulfhydryl microparticles are selected from surface-modified sulfhydryl polymer microparticles or surface-modified sulfhydryl inorganic microparticles.
In the present invention, the polyvinyl polymer means a polymer containing three or more vinyl groups.
In the invention, particle gel refers to close packing among particles, and cross-links among particles through a bridging component, so that the particle gel has inherent and regular space pores, which are different from the traditional gel blocks, wherein the traditional gel blocks have a chain cross-linked and inter-transmitted polymer network structure, and the packing of the particles and the pores among the particles are not existed.
In some embodiments, the surface-modified thiol-modified macromolecule particle is selected from one or more of surface-modified thiol-polystyrene particles, surface-modified thiol-polymethyl methacrylate particles, surface-modified thiol-polylactic acid-glycolic acid copolymer particles, surface-modified thiol-polyacrylamide particles, surface-modified thiol-dextran particles, surface-modified thiol-gelatin particles, surface-modified thiol-polyvinyl alcohol particles, surface-modified thiol-agarose particles.
In the invention, the preparation method of the various thiol-modified macromolecule microsphere can adopt the existing common thiol-modified method.
In some embodiments, the surface-modified thiol-modified macromolecule particle is prepared by reacting a thiol-modified macromolecule particle with a macromolecule particle having a double bond on the surface or is prepared by an emulsification reaction one-step method.
In some embodiments, the thiolated macromolecule is selected from one or more of thiolated hyaluronic acid, thiolated collagen, thiolated chitosan, thiolated gelatin, thiolated sodium alginate.
The sulfhydryl group on the sulfhydryl polymer and the double bond of hyperbranched polyethylene glycol diacrylate are subjected to Michael addition reaction, and in a water-in-oil emulsion system, excessive hydrophobic double bonds can be distributed on the surface of the generated polymer microsphere, so that the polymer microsphere with double bonds on the surface is obtained.
In some embodiments, the thiolated macromolecule has a molecular weight of 10 to 500 ten thousand, preferably 20 to 40 ten thousand, and a thiol grafting ratio of 0.1 to 0.9. Mu. Mol/mg.
In some embodiments, the polymer particles with double bonds on the surface are prepared from hyperbranched polyethylene glycol diacrylate and mercaptohyaluronic acid through a microfluidic technology.
In some embodiments, the hyperbranched polyethylene glycol diacrylate is prepared from polyethylene glycol diacrylate by RAFT living polymerization.
In some embodiments, the chain transfer agent used in RAFT living polymerization isThe structural formula of the polyethylene glycol diacrylate is
In some embodiments, the hyperbranched polyethylene glycol diacrylate has the structural formula: the double bond grafting rate is 10% -70%, x is 0.1-0.7, and y is 0.3-0.9.
In some embodiments, the thiol-modified hyaluronic acid has a monomeric unit of the structure:
in some embodiments, the molecular weight of the thiolated hyaluronic acid is 20-40 ten thousand.
And (3) carrying out Michael addition reaction on the double bonds on the polymer microsphere with the double bonds on the surface and the sulfhydryl groups in the sulfhydrylation reagent to obtain the polymer microsphere with the surface modified sulfhydryl groups. By this reaction, the surface of the polymer microsphere is converted from a double bond to a mercapto group.
In some embodiments, the cross-linking agent is selected from the group consisting of acrylated hyaluronic acid, acrylated polyethylene oxide-polypropylene oxide block copolymers, and the like, having two or more double bond polymers modified with acrylate bonds.
In some embodiments, the pH of the dispersion of the surface-modified thiol-modified polymeric beads is adjusted to neutral prior to the crosslinking reaction.
In some embodiments, the particle size of the surface-modified thiol-modified macromolecule microsphere is 5-500 micrometers, and the volume fraction of the surface-modified thiol-modified macromolecule microsphere in the dispersion liquid of the surface-modified thiol-modified macromolecule microsphere is 60-90%.
In some embodiments, the cross-linking agent is present in a mixture of a dispersion of surface-modified thiol-modified particles and the cross-linking agent at a mass volume concentration of 0.5wt% to 5wt%.
In some embodiments, the crosslinking reaction is performed at room temperature for a period of time ranging from 0.1 to 2 hours.
The invention also provides the particle gel prepared by the preparation method of the particle gel. Gel blocks can not be formed among particles of the particle gel, pores among the particles of the particle gel can not be blocked, the pores are uniformly distributed, the preparation condition of the particle gel is mild, and the biological performance is obviously improved.
The invention also provides the use of the aforementioned particulate gel for cell culture, bioprinting, regenerative medicine or drug delivery.
The inventors of the present application have found through studies that if a polymer microsphere having surface modified double bonds is subjected to a crosslinking reaction with a crosslinking agent having a multi-thiol group, the multi-thiol group on the crosslinking agent may spontaneously form a crosslinked structure, resulting in formation of crosslinked gel blocks between the particle gels, which are not in the particle state of the particle gels, nor have pores between the particles of the particle gels, resulting in blocking of the pores between the particles of the particle gels, and eventually making the mechanical properties of the obtained particle gels and the biological properties such as cell culture insufficient. The application synthesizes the macromolecule microsphere with double bonds on the surface through the water-in-oil emulsion dispersion method, then reacts with the sulfhydrylation reagent to make the macromolecule microsphere surface modified sulfhydryl, and simultaneously adopts the polyvinyl polymer as the cross-linking agent to carry out the cross-linking reaction to form the particle gel. The application fully considers the difference of the crosslinking conditions of the crosslinking agent with multi-mercapto and the crosslinking agent with polyvinyl, and applies the crosslinking agent to the polymer microsphere and the crosslinking agent for preparing the particle gel, thereby skillfully avoiding the formation of gel blocks among the particle gel and avoiding the blockage of the particle gel to different degrees.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
(1) The chemical covalent crosslinking among the particle units has mild implementation conditions and high crosslinking reaction activity
The particle gel system provided by the invention has the advantages that the surface of the high molecular microsphere with the surface modified sulfhydryl group has rich sulfhydryl functional groups, the high molecular microsphere can be subjected to Michael addition reaction with a high-activity polyvinyl cross-linking agent under a physiological condition, the conditions of irradiation, heating and the like are not required, and components such as an initiator, a catalyst and the like are not required to be additionally introduced, so that the particle gel system has the characteristic of excellent biocompatibility.
The thiol-modified macromolecule microsphere and the cross-linking agent can generate Michael addition reaction under physiological conditions (the pH value is neutral), the conditions such as photoinitiator, light radiation, heat radiation and the like are not involved in the cross-linking process, the whole cross-linking system does not involve the introduction of toxic reagents, and the prepared particle gel material is favorable for being used as a carrier of active components to embed the active components such as stem cells, exosomes and the like.
(2) Micro-scale pores with uniform interpenetration
The polyvinyl polymer is used as a crosslinking component, and can be effectively reacted with the high molecular microsphere with the surface modified sulfhydryl group under the neutral condition so as to effectively crosslink microsphere units; in addition, in the process, the cross-linking agent component can not generate self-crosslinking (does not meet the condition of self-crosslinking), so that the uniform interpenetrating micron-sized macroporous structure characteristic of the particle gel system can be effectively maintained, and gel blocks and blockage are avoided from being formed among particles of the particle gel.
The thiol groups on the thiol-modified macromolecule microsphere with different surfaces can be oxidized and self-crosslinked to form disulfide bonds, so that the connection between the microspheres can be enhanced.
(3) Easy to modify
The polyvinyl polymer is used as a crosslinking component, has multiple functional groups, can enhance the crosslinking efficiency, and the functional groups which do not participate in the reaction after the crosslinking reaction can enable the obtained particle gel to be subjected to grafting modification and the like in the subsequent application, so that the particle gel reactivity is endowed and the modification is facilitated, for example, small-molecule adhesion peptide RGD and the like can be added in the subsequent application of the particle gel, and the small-molecule peptide has sulfhydryl groups and can be grafted on unreacted active double bond groups, so that the adhesion of the particle gel is improved, and the particle gel can be used as a macroporous tissue engineering scaffold and can be used for cell 3D culture.
Drawings
FIG. 1 is a flow chart of the preparation of a particulate gel of the present invention;
FIG. 2 is a nuclear magnetic resonance chart of hyperbranched polyethylene glycol diacrylate obtained in preparation example 1;
FIG. 3 is a nuclear magnetic resonance diagram of the thiol-modified hyaluronic acid obtained in preparation example 2;
FIG. 4 is a nuclear magnetic resonance diagram of the multi-vinyl polymer cross-linking agent-acrylated hyaluronic acid obtained in preparation example 3;
FIG. 5 is a printed pattern obtained using the particle gel prepared in example 1 as a bio-ink;
FIG. 6 is a comparison of the results of the ink impregnation test of the particle gels prepared in example 1 and comparative example 1;
Fig. 7 is a gel forming time rheology test chart of the particle gels of example 1 and comparative example 1.
Detailed Description
The technical scheme of the invention is further described below with reference to the accompanying drawings.
Preparation example 1
Preparation of hyperbranched polyethylene glycol diacrylate (HB-PEGDA):
With DS (structural formula) ) Is RAFT reagent, 2' -azo-bis (2-methylnitrile) (AIBN) is used as initiator, and homopolymerized polyethylene glycol diacrylate PEGDA (structural formula is) (Average mn=575) (0.4 mol·l -1) as monomer, RAFT polymerization with feed in butanone at 70 ℃; [ PEGDA ]: [ DS ]: the molar ratio of [ AIBN ] is 25:1:1.4. the structural formula of the obtained HB-PEGDA is as follows: Wherein the double bond grafting rate is 34% (i.e. x is 0.34), and the nuclear magnetism characterization chart is shown in figure 2.
Preparation example 2
Preparation of thiol-modified hyaluronic acid (HA-SH)
Hyaluronic Acid (HA) (commercially available, having a molecular weight of 20-40 ten thousand), dithiodipropyl Dihydrazide (DTP) and Dithiothreitol (DTT) are used as main raw materials, wherein the molar ratio of HA, DTP and DTT is 1:2:12.HA and DTP are added with 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) to be activated for 5 hours under the acidic condition. Then NaOH is added to adjust the pH value of the reaction mixture to 7.0 to stop the reaction, after DTT is added, the pH value of the mixture is adjusted to 8.5, stirring is carried out for 24 hours, after the reaction is finished, the pH value of the reactant mixed solution is adjusted to 3.5, and dialysis is carried out for 4 days, thus obtaining the sulfhydryl modified hyaluronic acid (HA-SH), the structural formula of monomer units of which isThe molecular weight is 20-40 ten thousand, the grafting rate of mercapto group is 0.6 mu mol/mg, and the nuclear magnetic diagram is shown in figure 3.
Preparation example 3
Preparation of a polyvinyl Polymer-acrylated hyaluronic acid (HA-A)
Glycidyl acrylate and low molecular weight sodium hyaluronate HA (HA-TLM 20-40) are used as raw materials, triethylamine is used as an acid binding agent, nucleophilic addition reaction is carried out on the raw materials and the solvent DMF under the conditions of room temperature and alkalinity to generate the acrylated hyaluronic acid (HA-A), and the feeding mole ratio is glycidyl acrylate, triethylamine, sodium hyaluronate=50:50:1.
The structural formula of the obtained HA-A is as follows: the double bond grafting rate is 38%, and the nuclear magnetism characterization chart is shown in figure 4.
Example 1
The present example prepares a pellet gel:
1) Synthesizing a polymer microsphere with double bonds on the surface:
Dissolving surfactant (DOWSIL TM RSN-0749 Resin) in dimethyl silicone oil to prepare a solution with the mass fraction of 5%, and marking the solution as a continuous phase (oil phase); 20mg of thiolated hyaluronic acid (SH-HA) and 3mg of TCEP thiol reducer are dissolved in 1mL of deionized water to prepare a solution with SH-HA concentration of 2wt%, and the solution is recorded as a disperse phase 1; 100mg of hyperbranched polyethylene glycol diacrylate (HB-PEGDA) prepared in preparation example 1 was dissolved in deionized water to prepare a 10wt% solution designated as dispersed phase 2. Connecting the continuous phase, the disperse phase 1 and the disperse phase 2 prepared above with a microfluidic chip through a pipeline; the flow rate of the continuous phase is regulated to 24 mu L/min, the flow rate of the disperse phase 1 is regulated to 2 mu L/min, the flow rate of the disperse phase 2 is regulated to 2 mu L/min, monodisperse hydrogel micro-droplets are prepared by a water-in-oil emulsion dispersion method, after 2 hours of solidification, the microspheres are washed out, and the particle size distribution is 100-130 mu m.
2) Synthesizing high molecular microsphere with surface modified sulfhydryl group:
the thiol-modified hyaluronic acid obtained in preparation example 2 was dissolved in PBS buffer to a concentration of 1wt%; dispersing the polymer microsphere with double bonds on the surface, which is prepared in the step 1), in PBS, and removing the supernatant by 7000rpm for 5min to obtain the microsphere with compact arrangement. The 1wt% thiolated hyaluronic acid solution and the microspheres are mixed according to a volume ratio of 3:1, and stirring for 3h to enable the thiolated hyaluronic acid to be grafted on the surface of the microsphere. Then, 1mL of 0.1wt% DTT (dithiothreitol) was added to conduct a reaction for 12 hours to break the disulfide bond formed in the solution. Finally, adding a proper amount of PBS buffer solution, centrifuging at 7000rpm for 5min to remove supernatant, and washing for 3-4 times to obtain the surface-modified sulfhydryl polymer microsphere.
3) Preparing a particle gel:
The acrylated hyaluronic acid prepared in the preparation example 3 is dissolved in a dispersion liquid of surface modified sulfhydryl microsphere with volume fraction of 60%, the final mass volume concentration of the acrylated hyaluronic acid is 3wt% (w/v), the pH value of the mixed liquid is regulated to 7.0, and the mixture is left to fully react for 2 hours, so that the crosslinked particle gel material is obtained. The finally prepared particle gel can be used as a bio-ink material, and the pattern shown in fig. 5 can be obtained by using the finally prepared particle gel for bio-printing.
Comparative example 1
The dispersion liquid of the polymer microsphere with the surface modified double bonds and a cross-linking agent with multi-mercapto groups are adopted to carry out cross-linking reaction to prepare the particle gel material. The method comprises the following steps:
1) Synthesizing a polymer microsphere with double bonds on the surface:
Step 1) as in example 1;
2) Preparing a particle gel:
Basically, the same procedure as in step 3) of example 1 was followed except that the acrylated hyaluronic acid in step 3) of example 1 was replaced with the thiolated hyaluronic acid prepared in preparation example 2, and the surface-modified thiol-modified polymeric beads in step 3) of example 1 were replaced with the polymeric beads having double bonds on the surface prepared in step 1) described above.
The particulate gel materials obtained in example 1 and comparative example 1 were immersed in indian ink (commercially available under the brand PHYGENE) at room temperature for 1 hour, respectively, and the particle size of the ink particles was 10 -7～10-5 m; subsequently, the two kinds of pellet gel materials were taken out, and after washing with distilled water, the diffusion of the ink pellets inside the two kinds of pellet gels was observed, and the result is shown in fig. 5, wherein example 1 (denoted as pellet gel B in the drawing) is shown in the upper diagram of fig. 6, and comparative example 1 (denoted as pellet gel a in the drawing) is shown in the lower diagram of fig. 6.
It can be seen that comparative example 1 (pellet gel a) still has some transparency, while example 1 (pellet gel B) has been completely saturated with ink. Indicating that the diffusion rate of the ink inside the particle gel a of comparative example 1 is much less than that of the particle gel B of example 1. The cross-linking agent of the particle gel A is a thiolated polymer, and the thiolated polymer is oxidized and self-crosslinked while cross-linking the microspheres to form the particle gel, so that gel blocks can be formed to block the pores of the particle gel, and ink cannot be rapidly diffused into the gel particles in a short time. Finally, the particle gel A has certain transparency after being immersed in ink, while the cross-linking agent of the particle gel B in the embodiment 1 of the invention is a polyvinyl polymer, the polyvinyl polymer cross-linked microsphere forms particle gel, and the polyvinyl does not self-crosslink, so that a uniform porous particle gel material is obtained, and the uniform porous structure enables the ink to rapidly diffuse into the material.
The gel materials obtained in example 1 and comparative example 1 were subjected to rheological test, and the gel time and modulus after gel formation were compared, and the results are shown in fig. 7. The results show that the gel particles A of comparative example 1 are less efficient than those of gel particles B of example 1, and show a longer time to reach equilibrium modulus. In theory, the modulus of the particulate gel a and the particulate gel B should be substantially similar, since the gel particulate materials of both are substantially the same, and the cross-linking agent is also a modified hyaluronic acid material. In practice, however, it is shown from the figure that the modulus of the microgel a of comparative example 1 is continuously higher than that of the microgel B because gel masses are formed inside the microgel a, and the modulus of the gel masses is greater than that of the microgel. This reflects that part of the pores in the microgel a are blocked, i.e., a part of gel blocks are formed, while the crosslinking agent of the microgel B of example 1 is a polyvinyl polymer, and the polyvinyl polymer crosslinked microsphere forms the microgel, and at the same time, the polyvinyl does not self-crosslink, so that a uniform porous microgel material is obtained, so that the interior of the microgel B material is not blocked, uniform particles are formed, uniform pores exist in the interior, and the modulus is lower than that of the microgel a.
Claims (12)
1. A method for preparing a granular gel, which is characterized in that: the preparation method comprises the following steps: carrying out cross-linking reaction on dispersion liquid of particles with surface modified sulfhydryl groups and a cross-linking agent to prepare the particle gel; the cross-linking agent is a polyvinyl polymer; the surface-modified sulfhydryl microparticles are selected from surface-modified sulfhydryl polymer microparticles or surface-modified sulfhydryl inorganic microparticles.
2. The method for preparing a particulate gel according to claim 1, wherein: the high polymer particles with the surface modified sulfhydryl groups are selected from one or a plurality of surface modified sulfhydryl polystyrene particles, surface modified sulfhydryl polymethyl methacrylate particles, surface modified sulfhydryl polylactic acid-glycolic acid copolymer particles, surface modified sulfhydryl polyacrylamide particles, surface modified sulfhydryl dextran particles, surface modified sulfhydryl gelatin particles, surface modified sulfhydryl polyvinyl alcohol particles and surface modified sulfhydryl agarose.
3. The method for preparing a particulate gel according to claim 1, wherein: the surface-modified sulfhydryl polymer particles are prepared by reacting thiol-modified macromolecule particles with double bonds on the surface or by emulsifying thiol-modified macromolecule particles in one step.
4. A method of preparing a particulate gel according to claim 3, wherein: the thiolated macromolecule is selected from one or a combination of more of thiolated gelatin, thiolated hyaluronic acid, thiolated sodium alginate, thiolated collagen, thiolated heparin, thiolated pectin and thiolated polygalactonic acid; the molecular weight of the sulfhydrylation macromolecule is 10-500 ten thousand, and the sulfhydrylation grafting rate is 0.1-0.9 mu mol/mg.
5. A method of preparing a particulate gel according to claim 3, wherein: the high polymer particles with double bonds on the surfaces are prepared from hyperbranched polyethylene glycol diacrylate and sulfhydryl hyaluronic acid through a microfluidic technology.
6. The method for preparing a particulate gel according to claim 5, wherein: the hyperbranched polyethylene glycol diacrylate is prepared from polyethylene glycol diacrylate through RAFT active polymerization; preferably, the chain transfer agent used in RAFT polymerization isThe structural formula of the polyethylene glycol diacrylate isMore preferably, the hyperbranched polyethylene glycol diacrylate has the structural formula: The double bond grafting rate is 10-70%, x is 0.1-0.7, and y is 0.3-0.9; the structure of the monomer unit of the sulfhydrylation hyaluronic acid is as follows: and the molecular weight of the sulfhydryl hyaluronic acid is 20-40 ten thousand.
7. The method for preparing a particulate gel according to claim 1, wherein: the cross-linking agent is selected from acrylated hyaluronic acid and/or acrylated polyethylene oxide-polypropylene oxide block copolymer, and the double bond grafting rate of the cross-linking agent is 10-50%.
8. The method for preparing a particulate gel according to claim 1, wherein: the pH of the dispersion of the thiol-modified macromolecule particle is adjusted to be neutral before the cross-linking reaction.
9. The method for preparing a particulate gel according to claim 1, wherein: the particle size of the surface-modified sulfhydryl polymer particles is 5-500 micrometers, and the volume fraction of the surface-modified sulfhydryl polymer particles in the dispersion liquid of the surface-modified sulfhydryl polymer particles is 60-90%.
10. The method for preparing a particulate gel according to claim 1, wherein: in the mixture of the dispersion liquid of the particles with the surface modified sulfhydryl groups and the cross-linking agent, the mass volume concentration of the cross-linking agent is 0.5-5 wt%.
11. A particulate gel prepared by the method of any one of claims 1 to 10.
12. Use of the particulate gel of claims 1-10 for cell culture, bioprinting, regenerative medicine or drug delivery.
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