CN117534851A - Indocyanine green hydrogel fluorescence calibration plate and preparation method and application thereof - Google Patents
Indocyanine green hydrogel fluorescence calibration plate and preparation method and application thereof Download PDFInfo
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- CN117534851A CN117534851A CN202410032897.XA CN202410032897A CN117534851A CN 117534851 A CN117534851 A CN 117534851A CN 202410032897 A CN202410032897 A CN 202410032897A CN 117534851 A CN117534851 A CN 117534851A
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- polyvinyl alcohol
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- 239000000017 hydrogel Substances 0.000 title claims abstract description 238
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 title claims abstract description 104
- 229960004657 indocyanine green Drugs 0.000 title claims abstract description 104
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 239000000499 gel Substances 0.000 claims abstract description 153
- 239000000243 solution Substances 0.000 claims abstract description 152
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 76
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 76
- 239000000661 sodium alginate Substances 0.000 claims abstract description 76
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 76
- 239000004115 Sodium Silicate Substances 0.000 claims abstract description 67
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 claims abstract description 67
- 229910052911 sodium silicate Inorganic materials 0.000 claims abstract description 67
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- 238000002791 soaking Methods 0.000 claims abstract description 25
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims abstract description 22
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 238000004140 cleaning Methods 0.000 claims abstract description 9
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- 238000003756 stirring Methods 0.000 claims description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 52
- 238000002156 mixing Methods 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 37
- 239000008367 deionised water Substances 0.000 claims description 22
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- 239000002243 precursor Substances 0.000 claims description 22
- 238000010438 heat treatment Methods 0.000 claims description 17
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 7
- 230000003287 optical effect Effects 0.000 claims description 7
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 7
- 238000010907 mechanical stirring Methods 0.000 claims description 6
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims description 5
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 229910021538 borax Inorganic materials 0.000 claims description 5
- ZIUHHBKFKCYYJD-UHFFFAOYSA-N n,n'-methylenebisacrylamide Chemical compound C=CC(=O)NCNC(=O)C=C ZIUHHBKFKCYYJD-UHFFFAOYSA-N 0.000 claims description 5
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- 239000004328 sodium tetraborate Substances 0.000 claims description 5
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- 125000003277 amino group Chemical group 0.000 description 6
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- 238000006116 polymerization reaction Methods 0.000 description 6
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 238000010382 chemical cross-linking Methods 0.000 description 5
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- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 2
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 2
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- NJSSICCENMLTKO-HRCBOCMUSA-N [(1r,2s,4r,5r)-3-hydroxy-4-(4-methylphenyl)sulfonyloxy-6,8-dioxabicyclo[3.2.1]octan-2-yl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@H]1C(O)[C@@H](OS(=O)(=O)C=2C=CC(C)=CC=2)[C@@H]2OC[C@H]1O2 NJSSICCENMLTKO-HRCBOCMUSA-N 0.000 description 1
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Classifications
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- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
-
- 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
- C08J2305/04—Alginic acid; Derivatives thereof
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- 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
- C08J2401/00—Characterised by the use of cellulose, modified cellulose or cellulose derivatives
- C08J2401/02—Cellulose; Modified cellulose
- C08J2401/04—Oxycellulose; Hydrocellulose
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- 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
- C08J2429/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal, or ketal radical; Hydrolysed polymers of esters of unsaturated alcohols with saturated carboxylic acids; Derivatives of such polymer
- C08J2429/02—Homopolymers or copolymers of unsaturated alcohols
- C08J2429/04—Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic 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
- C08J2433/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers
- C08J2433/24—Homopolymers or copolymers of amides or imides
- C08J2433/26—Homopolymers or copolymers of acrylamide or methacrylamide
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K3/00—Use of inorganic substances as compounding ingredients
- C08K3/34—Silicon-containing compounds
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/36—Sulfur-, selenium-, or tellurium-containing compounds
- C08K5/41—Compounds containing sulfur bound to oxygen
- C08K5/42—Sulfonic acids; Derivatives thereof
Abstract
The invention belongs to the technical field of fluorescent calibration plates, and provides an indocyanine green hydrogel fluorescent calibration plate, and a preparation method and application thereof, wherein the indocyanine green hydrogel fluorescent calibration plate comprises the following components: dissolving sodium alginate in a polyvinyl alcohol solution, adding acrylamide and nanocellulose suspension into the mixed solution, and then adding an initiator and a cross-linking agent to carry out cross-linking reaction to obtain a hydrogel solution; adding indocyanine green into the hydrogel solution to obtain a mixed gel solution; freezing at low temperature, and thawing at room temperature to obtain intermediate gel; then soaking in ethanol water solution of sodium silicate, taking out and cleaning to obtain hydrogel; preparing multiple groups of hydrogel containing indocyanine green, respectively injecting into sample tubes, fixing in porous plates, and repeating freezing and thawing for at least three times. The invention can greatly improve the stability of indocyanine green in a hydrogel system, and is not easy to generate photobleaching and degradation, thereby maintaining the long-term stable fluorescence intensity of the fluorescence calibration plate.
Description
Technical Field
The invention belongs to the technical field of fluorescent calibration plates, and relates to an indocyanine green hydrogel fluorescent calibration plate, and a preparation method and application thereof.
Background
The indocyanine green solution is easy to be subjected to photobleaching, degradation and the like, so that the concentration gradient solution of indocyanine green cannot be stably stored and cannot be reused, and the indocyanine green solution is required to be prepared again each time the fluorescence detection function and the sensitivity of the optical operation navigation system are tested, so that the indocyanine green is inevitably wasted; in addition, because the indocyanine green hydrogel has poor mechanical properties, the indocyanine green hydrogel cannot be stored for a long time, and the working efficiency of the fluorescence navigation operation process is affected.
CN115819667a discloses a hydrogel-based indocyanine green fluorescent calibration plate, and a preparation method and application thereof, comprising the following steps: carrying out polymerization reaction on a mixed solution containing a polymerization monomer, a cross-linking agent, an initiator and water to generate a hydrogel solution; wherein the polymerized monomers comprise acrylamide and diallyl dimethyl ammonium chloride; adding indocyanine green into the hydrogel solution to obtain a hydrogel solution containing indocyanine green; and solidifying and forming the hydrogel solution containing indocyanine green to obtain the hydrogel-based indocyanine green fluorescence calibration plate. However, the fluorescent calibration plate prepared by the technical scheme has poor mechanical property and stability, and cannot meet the use requirement.
Therefore, improvement on the existing preparation process of indocyanine green hydrogel fluorescent calibration plate is needed to improve the mechanical property and stability of the fluorescent calibration plate.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide the indocyanine green hydrogel fluorescent calibration plate, and the preparation method and the application thereof.
To achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a preparation method of an indocyanine green hydrogel fluorescent calibration plate, which comprises the following steps:
dissolving sodium alginate in a polyvinyl alcohol solution, and uniformly mixing to obtain a mixed solution; sequentially adding acrylamide and nanocellulose suspension into the mixed solution, and uniformly mixing to obtain a precursor solution; adding an initiator and a cross-linking agent into the precursor solution, uniformly mixing and carrying out a cross-linking reaction to obtain a hydrogel solution;
(II) adding indocyanine green into the hydrogel solution obtained in the step (I), uniformly mixing, and then performing ultrasonic defoaming to obtain a mixed gel solution; freezing the mixed gel solution at low temperature until the mixed gel solution is completely solidified, and then thawing the mixed gel solution at room temperature to obtain intermediate gel; soaking the intermediate gel in an ethanol water solution of sodium silicate, and taking out and cleaning after soaking to obtain hydrogel;
and (III) preparing a plurality of groups of hydrogels containing indocyanine green with different concentrations, respectively injecting the hydrogels into independent sample tubes, fixing the sample tubes in a porous plate, freezing the porous plate in a low-temperature environment, then thawing the porous plate at room temperature, and repeatedly freezing and thawing the porous plate at least three times to obtain the indocyanine green hydrogel fluorescence calibration plate.
The sodium alginate has excellent biocompatibility and water absorption and moisture retention, and the raw materials are wide in source, safe, nontoxic and degradable, and have wider and wider application in the aspect of biological materials. However, sodium alginate hydrogel has the defects of poor gel controllability and low mechanical strength, and when the sodium alginate hydrogel is used alone, the practical application requirements of people on the hydrogel are often difficult to meet, so that the application range of the sodium alginate hydrogel is greatly limited. According to the invention, polyvinyl alcohol and sodium alginate are compounded through an interpenetrating network technology, sodium alginate molecules enter a polyvinyl alcohol network and are physically entangled with the polyvinyl alcohol molecules, so that the cross-linking point density of the polyvinyl alcohol hydrogel is destroyed, and a first semi-interpenetrating gel network is formed.
The acrylamide monomer is subjected to thermal initiation free radical polymerization under the action of an initiator and a cross-linking agent to form a covalent cross-linked polyacrylamide network structure, linear macromolecules of sodium alginate are inserted into the covalent cross-linked polyacrylamide network structure to form a second semi-interpenetrating gel network, hydrogen bonds are formed between amino groups of polyacrylamide and hydroxyl groups of sodium alginate, intermolecular acting force between polyacrylamide molecules and sodium alginate molecules is enhanced, and therefore mechanical properties of the second semi-interpenetrating gel network are improved.
According to the invention, the polyvinyl alcohol/sodium alginate is adopted as a first semi-interpenetrating gel network, the polyacrylamide/sodium alginate is adopted as a second semi-interpenetrating gel network, a semi-interpenetrating double-network gel structure consisting of the first semi-interpenetrating gel network and the second semi-interpenetrating gel network is formed, a hydrogen bond between a polyvinyl alcohol molecular chain and a polyacrylamide molecular chain in the double-network hydrogel is adopted as a sacrificial bond, so that the external load can be effectively resisted, and the hydrogel can still quickly recover after repeated stretching or loading.
According to the invention, nanocellulose is added into a semi-interpenetrating double-network gel system of sodium alginate/polyvinyl alcohol/acrylamide, so that the indocyanine green hydrogel fluorescent calibration plate which is soft in texture, can keep a certain shape and is stable for a long time is prepared. According to the invention, the nanocellulose, the polyvinyl alcohol and the polyacrylamide are subjected to physical crosslinking, the nanocellulose can be used as a polymer reinforced phase, a large number of amino groups exist on a polyacrylamide molecular chain, a large number of hydroxyl groups exist on a polyvinyl alcohol molecular chain, and hydrogel can be formed through physical or chemical crosslinking. The surface of the nanocellulose contains a large number of hydroxyl groups, has good dispersibility in water-soluble polymers, can be combined with hydroxyl groups on a polyvinyl alcohol molecular chain and amino groups on a polyacrylamide molecular chain to form firm hydrogen bonds, and plays a role in nano reinforcement.
The invention combines freeze thawing cycle and sodium silicate salting out to prepare the hydrogel with compact cortex and porous inner layer. When the intermediate gel is soaked in the ethanol aqueous solution of sodium silicate for a period of time, salting-out effect and polarization effect can occur between the sodium silicate and the sodium alginate/polyvinyl alcohol/acrylamide gel system, under the effect of the salting-out effect, the sodium alginate/polyvinyl alcohol/acrylamide gel system is dehydrated, and in the dehydration process, the gel system forms a microcrystalline structure formed by orderly stacked hydrogen bonds. Under the effect of polarization effect, the alkali sodium silicate can enhance the interaction of hydroxyl functional groups in a sodium alginate/polyvinyl alcohol/acrylamide gel system by in-situ doping, and ethanol in the solution is deprotonated in an alkali environment, so that the hydroxyl functional groups obtain polarization enhancement effect, and the dipole-dipole interaction is shown, thereby enhancing the stability of microcrystalline tissues. By virtue of salting-out effect and polarization effect between sodium silicate and intermediate gel, strong aggregation of polymer chains on the surface of the intermediate gel and formation of microcrystals can be rapidly initiated, and a more compact and stable skin layer with a directional porous network structure is obtained, on one hand, the formation of the compact skin layer can be used as a protective barrier of indocyanine green hydrogel, so that the stability of indocyanine green hydrogel in different solvent environments is improved; on the other hand, the cortex has a compact network structure, so that the mechanical property of the hydrogel is greatly improved. When the compact cortex is formed, the penetration effect of the ethanol aqueous solution of sodium silicate on the gel is gradually weakened, and silicate is difficult to continuously penetrate into the middle gel, so that the obtained hydrogel has a porous semi-interpenetrating double-network gel structure.
The solvent of the coagulation bath adopted by the invention is ethanol water solution, and the ethanol can effectively control the swelling degree of the hydrogel in the ionic crosslinking process, and has no other adverse effects on the ionic crosslinking process. The synergistic effect of sodium silicate and ethanol ensures that the porous network structure of the formed hydrogel intermediate layer is more uniform and regular, the network pore diameter is reduced, the pore density is increased, and the mechanical property is greatly improved. The porous network structure with uniform crosslinking provides a firm structural foundation for the excellent water absorption and moisture retention of the hydrogel, and can also endow the hydrogel with good mechanical elasticity.
According to the invention, after indocyanine green is added into the hydrogel, the hydrogel-based indocyanine green fluorescent calibration plate is prepared through freeze thawing cycle curing molding, the hydrogel-based indocyanine green has a fixed shape, the hydrogel-based indocyanine green fluorescent calibration plate prepared by the preparation method provided by the invention does not influence the fluorescent property of indocyanine green, and the stability of indocyanine green in a hydrogel system can be greatly improved, photobleaching and degradation are not easy to occur, so that the fluorescent intensity of the fluorescent calibration plate which is stable for a long time is maintained, and convenience is provided for detecting the fluorescent function and sensitivity of an optical operation navigation system.
As a preferable technical scheme of the invention, in the step (I), the polyvinyl alcohol solution is prepared by adopting the following method:
and dissolving the polyvinyl alcohol in deionized water, heating the deionized water, mixing and stirring until the polyvinyl alcohol is completely dissolved, and obtaining the polyvinyl alcohol solution.
In some alternative examples, the deionized water is heated to 80-90 ℃, such as 80 ℃, 81 ℃, 82 ℃, 83 ℃, 84 ℃, 85 ℃, 86 ℃, 87 ℃, 88 ℃, 89 ℃, or 90 ℃, but is not limited to the recited values, and other non-recited values within the range are equally applicable.
In some optional examples, the time of mixing and stirring the polyvinyl alcohol in the deionized water is 10-30 min, for example, 10min, 12min, 14min, 16min, 18min, 20min, 22min, 24min, 26min, 28min or 30min, but not limited to the recited values, and other non-recited values in the range of values are equally applicable.
In some alternative examples, the concentration of the polyvinyl alcohol in the polyvinyl alcohol solution is 10 to 20g/mL, for example, 10g/mL, 11g/mL, 12g/mL, 13g/mL, 14g/mL, 15g/mL, 16g/mL, 17g/mL, 18g/mL, 19g/mL or 20g/mL, but not limited to the recited values, and other non-recited values within the range of values are equally applicable.
In some optional examples, the mass ratio of the sodium alginate to the polyvinyl alcohol in the polyvinyl alcohol solution is 1 (0.1-0.3), for example, may be 1:0.1, 1:0.12, 1:0.14, 1:0.16, 1:0.18, 1:0.2, 1:0.22, 1:0.24, 1:0.26, 1:0.28 or 1:0.3, but is not limited to the recited values, and other non-recited values within the range of values are equally applicable.
According to the invention, the sodium alginate and the polyvinyl alcohol are compounded to form the first semi-interpenetrating gel network, and in the mixing process, the linear macromolecular chains of the sodium alginate penetrate through the polyvinyl alcohol network, so that gaps of the polyvinyl alcohol network are filled, and the linear macromolecular chains of the sodium alginate and the polyvinyl alcohol are mutually entangled to jointly resist the action of external force, so that the mechanical property of the hydrogel is improved. However, sodium alginate cannot be added in an unlimited manner, and the mass ratio of sodium alginate to polyvinyl alcohol is particularly limited to 1 (0.1-0.3).
With the increase of the addition amount of the sodium alginate, the density of entanglement points among linear macromolecular chains of the sodium alginate is increased, and the intermolecular van der Waals force and the hydrogen bond effect jointly cause the increase of the viscosity of the mixed solution. When the addition amount of sodium alginate in the mixed solution exceeds the upper limit of the range defined by the invention, the viscosity of the mixed solution is too high, the fluidity is poor, the preparation of hydrogel is not facilitated, and meanwhile, the subsequent dispersion uniformity of acrylamide and nanocellulose is also adversely affected.
Secondly, when the addition amount of the sodium alginate is within the mass ratio range defined by the invention, as the sodium alginate macromolecules contain a large amount of carboxyl groups, the sodium alginate macromolecules have stronger hydrophilicity and have promotion effect on the swelling of the hydrogel, and therefore, the equilibrium swelling ratio of the hydrogel is gradually increased along with the increase of the addition amount of the sodium alginate. However, as the addition amount of sodium alginate is continuously increased and exceeds the upper limit of the range defined by the invention, the entanglement degree of the sodium alginate macromolecular chains in the first half interpenetrating gel network is increased, so that the first half interpenetrating gel network structure is too compact, the space for containing water molecules is reduced, the free movement of the water molecules is not facilitated, and the equilibrium swelling ratio of the hydrogel is reduced.
And when the adding amount of the sodium alginate is within the mass ratio range defined by the invention, the density of the first half interpenetrating gel network structure is gradually increased along with the increasing of the adding amount of the sodium alginate, and the stress is dispersed under the action of external force, so that the tensile strength and the elongation at break of the hydrogel are both improved. However, when the adding amount of sodium alginate is continuously increased and exceeds the upper limit of the range defined by the invention, the first half interpenetrating gel network structure is relatively perfect, the adding amount of sodium alginate is continuously increased, so that the structure of the first half interpenetrating gel network is too compact, the mobility of a molecular chain is reduced, and the molecular chain cannot freely move under the action of external force, so that the brittleness of the hydrogel is improved, and the elongation at break is reduced.
In some alternative examples, the sodium alginate is mixed and stirred in the polyvinyl alcohol solution for 1-5 h, for example, 1.0h, 1.5h, 2.0h, 2.5h, 3.0h, 3.5h, 4.0h, 4.5h or 5.0h, but not limited to the recited values, and other non-recited values within the range of values are equally applicable.
As a preferred technical scheme of the invention, in the step (I), the precursor solution is prepared by adopting the following method:
dispersing acrylamide in a mixed solution, heating, mixing and stirring the mixed solution until the acrylamide is completely dissolved, maintaining the temperature of the mixed solution unchanged and continuously stirring, simultaneously adding the nanocellulose suspension into the mixed solution, and continuously stirring to obtain the precursor solution.
In some alternative examples, the mass ratio of the acrylamide to the polyvinyl alcohol is (0.3-0.5): 1, for example, 0.3:1, 0.32:1, 0.34:1, 0.36:1, 0.38:1, 0.4:1, 0.42:1, 0.44:1, 0.46:1, 0.48:1 or 0.5:1, but not limited to the recited values, and other non-recited values within the range of values are equally applicable.
The invention is particularly limited in that the mass ratio of the acrylamide to the polyvinyl alcohol is (0.3-0.5): 1, when the addition amount of the acrylamide is lower than the lower limit of the mass ratio range limited by the invention, the free radical polymerization reaction is insufficient, the acrylamide monomer is not enough to effectively crosslink, the crosslinking degree is lower, and the structure of the formed second semi-interpenetrating gel network is imperfect. As the water molecules enter the hydrogel and swell, the second semi-interpenetrating gel network part deforms and collapses, and the water molecules cannot be fixed in the second semi-interpenetrating gel network structure with low crosslinking, so that the equilibrium swelling of the prepared hydrogel is low. With the increase of the addition amount of the acrylamide, the number of the acrylamide monomers in unit volume is increased, the number of the effective acrylamide monomers participating in chemical crosslinking is increased, chemical crosslinking points of the second semi-interpenetrating gel network are increased, and enough crosslinking points can support the integrity of the second semi-interpenetrating gel network structure in a swelling state, so that the equilibrium swelling ratio of the hydrogel is increased. However, when the amount of acrylamide added is further increased and exceeds the upper limit of the mass ratio range defined in the present invention, the crosslink density of the second semi-interpenetrating gel network structure is too high, so that the equilibrium swelling ratio of the hydrogel tends to decrease.
In addition, as the addition amount of the acrylamide is increased, the tensile strength and the elongation at break of the hydrogel are increased, and the effective amount of the acrylamide monomer participating in chemical crosslinking is increased, so that the formed second semi-interpenetrating gel network structure is more perfect, and the stress is uniformly distributed due to the motion rearrangement of the polyacrylamide molecular chain segments in the second semi-interpenetrating gel network under the action of external force, so that the occurrence and the extension of cracks can be effectively prevented. However, when the addition amount of acrylamide is continuously increased and exceeds the upper limit of the mass ratio range defined by the invention, the breaking elongation of the hydrogel tends to be reduced, because the acrylamide monomer is excessively crosslinked to reduce the activity of a molecular chain of the polyacrylamide with the continuous increase of the addition amount of the acrylamide, and local stress is easily generated under the action of external force to damage the structure of the hydrogel, so that the toughness of the hydrogel is reduced.
In some alternative examples, the mixture is heated to 40 to 50 ℃, for example, 40 ℃, 41 ℃, 42 ℃, 43 ℃, 44 ℃, 45 ℃, 46 ℃, 47 ℃, 48 ℃, 49 ℃, or 50 ℃, but the mixture is not limited to the recited values, and other non-recited values within the range are equally applicable.
In some alternative examples, the acrylamide is added and stirred for 1-5 hours until the acrylamide is completely dissolved, for example, 1.0h, 1.5h, 2.0h, 2.5h, 3.0h, 3.5h, 4.0h, 4.5h or 5.0h, but not limited to the recited values, and other non-recited values within the range of values are equally applicable.
In some alternative examples, the mass fraction of the nanocellulose suspension is 1.5-3 wt%, such as 1.5wt%, 1.6wt%, 1.7wt%, 1.8wt%, 1.9wt%, 2.0wt%, 2.1wt%, 2.2wt%, 2.3wt%, 2.4wt%, 2.5wt%, 2.6wt%, 2.7wt%, 2.8wt%, 2.9wt%, or 3.0wt%, but not limited to the recited values, and other non-recited values within the range of values are equally applicable.
In some alternative examples, the nanocellulose suspension is added in an amount of: 15 to 20mL of nanocellulose suspension is added to each gram of polyvinyl alcohol, for example, 15mL, 15.5mL, 16mL, 16.5mL, 17mL, 17.5mL, 18mL, 18.5mL, 19mL, 19.5mL or 20mL can be added correspondingly, but the nanocellulose suspension is not limited to the listed values, and other values not listed in the range of the values are applicable.
The gel structure formed by the independent polyvinyl alcohol is soft and inelastic, and after the nanocellulose is added, the mechanical property of the hydrogel can be effectively improved, because the polyvinyl alcohol is only chemically combined into hydrogen bonds when the nanocellulose is not added, the structure of the first semi-interpenetrating gel network is loose and not compact. After the nano-cellulose is added, the nano-cellulose, the polyvinyl alcohol and the acrylamide can be mutually entangled together through the combined action of chemical and physical crosslinking to form an interpenetrating polymer three-dimensional network structure, so that the mechanical property of the hydrogel is greatly improved.
In addition, the water retention performance of the hydrogel can be greatly improved after the nanocellulose is added, and the nanocellulose forms a three-dimensional network structure through physical cross winding, so that the hydrogel is stable in structure, the density is increased, and the loss of water molecules is limited; in addition, as the surface of the nanocellulose has a large number of hydrophilic functional groups, water molecules can be bound in a three-dimensional network structure, so that the high-molecular hydrogel is endowed with good water retention performance.
In some alternative examples, the nanocellulose suspension is added and then stirred for 0.5-1.5 h, for example, 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1.0h, 1.1h, 1.2h, 1.3h, 1.4h or 1.5h, but not limited to the recited values, and other non-recited values within the range of values are equally applicable.
As a preferable technical scheme of the invention, in the step (I), the initiator is any one or a combination of at least two of ammonium persulfate, tetramethyl ethylenediamine and potassium persulfate.
In some alternative examples, the initiator may be added in an amount of 2-5 wt% based on the mass of acrylamide, for example, but not limited to the recited values, 2.0wt%, 2.2wt%, 2.4wt%, 2.6wt%, 2.8wt%, 3.0wt%, 3.2wt%, 3.4wt%, 3.6wt%, 3.8wt%, 4.0wt%, 4.2wt%, 4.4wt%, 4.6wt%, 4.8wt%, or 5.0wt%, and other non-recited values within the range of values are equally applicable.
The acrylamide is subjected to free radical polymerization reaction under the action of an initiator to form a covalent cross-linked macromolecular network structure, and the dosage of the initiator directly influences the cross-linking degree and the polymerization molecular weight of the second semi-interpenetrating gel network and finally influences the mechanical property of the hydrogel.
As the amount of initiator added increases, the equilibrium swelling ratio of the hydrogel tends to increase and then decrease. When the addition amount of the initiator is less than 2wt%, the amount of the generated activated free radicals is too small, the polymerization reaction of the acrylamide monomer is not fully initiated, and the aim of effectively initiating the crosslinking is not achieved, so that the formed second semi-interpenetrating gel network structure is imperfect, and the equilibrium swelling ratio of the hydrogel is finally too low. With the increase of the addition amount of the initiator, the reaction for initiating free radical polymerization is enhanced, the second semi-interpenetrating gel network structure tends to be perfect, and the equilibrium swelling ratio of the hydrogel is increased. When the addition amount of the initiator exceeds 5wt%, the initiated polymerization reaction of the acrylamide monomer is increased, covalent crosslinking points are increased, the formed second semi-interpenetrating gel network structure is too compact, the size of the hydrogel is reduced, and the equilibrium swelling ratio of the hydrogel is reduced.
In addition, as the addition amount of the initiator is increased, the tensile strength and the elongation at break of the hydrogel are also increased, and because the acrylamide monomer is subjected to free radical polymerization reaction under the action of the initiator, more free radicals can be activated to generate along with the increase of the addition amount of the initiator, so that the polymerization reaction of the acrylamide monomer is more complete, the covalent crosslinking molecular chain is more regular, the formed polyacrylamide covalent crosslinking network is more perfect, the stress dispersion is more uniform when the external force acts, and finally the tensile strength and the elongation at break of the hydrogel are increased.
In some alternative examples, the cross-linking agent is any one or a combination of at least two of N, N' -methylenebisacrylamide, epichlorohydrin, glutaraldehyde, borax, polyethylene glycol.
In some alternative examples, the amount of the crosslinking agent added is 3-10 wt% of the mass of acrylamide, for example, 3.0wt%, 3.5wt%, 4.0wt%, 4.5wt%, 5.0wt%, 5.5wt%, 6.0wt%, 6.5wt%, 7.0wt%, 7.5wt%, 8.0wt%, 8.5wt%, 9.0wt%, 9.5wt% or 10.0wt%, but is not limited to the recited values, and other non-recited values within the range of values are equally applicable.
As a preferable technical scheme of the invention, in the step (II), the indocyanine green and the hydrogel solution are mixed in a mechanical stirring mode.
In some alternative examples, the mechanical stirring time is 1-3 h, for example, 1.0h, 1.2h, 1.4h, 1.6h, 1.8h, 2.0h, 2.2h, 2.4h, 2.6h, 2.8h or 3.0h, but not limited to the recited values, and other non-recited values within the range of values are equally applicable.
In some alternative examples, the mechanical stirring speed is 60-120 rpm, for example, 60rpm, 65rpm, 70rpm, 75rpm, 80rpm, 85rpm, 90rpm, 95rpm, 100rpm, 105rpm, 110rpm, 115rpm or 120rpm, but not limited to the recited values, and other non-recited values within the range of values are equally applicable.
In some alternative examples, the ultrasonic power used for the ultrasonic bubble removal is 3-5 kW, which may be, for example, 3.0kW, 3.2kW, 3.4kW, 3.6kW, 3.8kW, 4.0kW, 4.2kW, 4.4kW, 4.6kW, 4.8kW or 5.0kW, but not limited to the recited values, and other non-recited values within the range of values are equally applicable.
In some alternative examples, the time for ultrasonic bubble removal is 10-20 min, for example, 10min, 11min, 12min, 13min, 14min, 15min, 16min, 17min, 18min, 19min or 20min, but not limited to the recited values, and other non-recited values within the range of values are equally applicable.
In the step (ii), the mixed gel solution has a low-temperature freezing temperature of-20 to-10 ℃, for example, -20 ℃, -19 ℃, -18 ℃, -17 ℃, -16 ℃, -15 ℃, -14 ℃, -13 ℃, -12 ℃, -11 ℃ or-10 ℃, but not limited to the recited values, and other non-recited values within the range of values are equally applicable.
In some alternative examples, the mixed gel solution may have a low temperature freezing time of 4-6 h, for example, 4.0h, 4.2h, 4.4h, 4.6h, 4.8h, 5.0h, 5.2h, 5.4h, 5.6h, 5.8h, or 6.0h, but not limited to the recited values, and other non-recited values within the range of values are equally applicable.
In some alternative examples, the thawing time of the mixed gel solution at room temperature is 3-5 h, for example, 3.0h, 3.2h, 3.4h, 3.6h, 3.8h, 4.0h, 4.2h, 4.4h, 4.6h, 4.8h or 5.0h, but not limited to the recited values, and other non-recited values within the range of values are equally applicable.
In the step (ii), the mass fraction of sodium silicate in the aqueous ethanol solution of sodium silicate is 30 to 40wt%, for example, 30wt%, 31wt%, 32wt%, 33wt%, 34wt%, 35wt%, 36wt%, 37wt%, 38wt%, 39wt% or 40wt%, but the present invention is not limited to the above-mentioned values, and other values not shown in the above-mentioned values are equally applicable.
The hydrogel prepared by the method consists of a compact-structure cortex and a loose porous middle layer, wherein in the soaking process, polyvinyl alcohol on the surface of the middle gel is firstly contacted with sodium silicate, and salting-out effect leads to the surface of the middle gel to be dehydrated to form the compact-structure cortex; meanwhile, due to the strong alkalinity of sodium silicate, the-OH in the polyvinyl alcohol is induced to be polarized, so that the hydrogen bond interaction between polyvinyl alcohol molecular chains is enhanced, and the compact structure of the cortex is further stabilized; finally, as the molecular size of the sodium silicate is larger, the sodium silicate is difficult to further diffuse into the hydrogel along with the improvement of the density of the cortex, and the hydrogel with the compact cortex is finally obtained.
The compact structure of the cortex has swelling stability due to ordered polarization hydrogen bond crosslinking, and the hydrogel can maintain good mechanical properties even after being immersed into strong acid solution or strong alkali solution for a long time under the protection of the cortex. The inside of the hydrogel is a semi-interpenetrating double-network gel consisting of a first semi-interpenetrating gel network of polyvinyl alcohol/sodium alginate and a second semi-interpenetrating gel network of polyacrylamide/sodium alginate, the structure has a loose macroporous structure, can lock a large amount of indocyanine green, can ensure that the indocyanine green is stably dispersed in the structure, and the synergistic effect of the structure and the crosslinking degree ensures that the indocyanine green hydrogel can bear complex mechanical and environmental loads.
As the concentration of sodium silicate increases, resulting in an increase in the thickness of the dense skin layer formed, the increase in skin layer thickness results in a substantial increase in the mechanical properties of the hydrogel. When the hydrogel forms a dense cortex due to the coupling effect of sodium silicate, the permeation effect of sodium silicate on the hydrogel is gradually weakened, and even if the concentration of sodium silicate is continuously increased, the thickness of the formed dense cortex is not continuously increased. In addition, when the concentration of sodium silicate is too high, the formed skin layer is too thick, and accordingly, the pores of the semi-interpenetrating double network gel with the high hydration porous structure in the hydrogel are reduced, and the volume of a cavity capable of storing indocyanine green is reduced.
In some alternative examples, the volume ratio of ethanol to water in the aqueous ethanol solution of sodium silicate is 1 (2-3), for example, may be 1:2, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29 or 1:3, but is not limited to the recited values, and other non-recited values within the range of values are equally applicable.
The invention is particularly limited in that the volume ratio of the ethanol to the water is 1 (2-3), and the ethanol can control the swelling degree of the hydrogel in the soaking process of the intermediate gel. As the ethanol content increases, the swelling degree of the intermediate gel is reduced, the gel size of the prepared hydrogel is reduced, the gel structure in unit area is more compact, and molecules which do not undergo a crosslinking reaction in the hydrogel are not easily dissolved out; in addition, as the ethanol content increases, the water content in the solution is relatively reduced, so that the swelling degree of the hydrogel in the soaking process is controlled, the water content in the hydrogel structure in unit volume is reduced, the crosslinking density of the gel network is improved, and the equilibrium swelling ratio of the hydrogel is reduced.
In some alternative examples, the intermediate gel is immersed in the aqueous ethanol solution of sodium silicate for 1-5 h, for example, 1.0h, 1.5h, 2.0h, 2.5h, 3.0h, 3.5h, 4.0h, 4.5h or 5.0h, but not limited to the recited values, and other non-recited values within the range of values are equally applicable.
The intermediate gel can have obvious swelling effect in the ethanol water solution of sodium silicate, firstly, water molecules in the ethanol water solution of sodium silicate diffuse inwards from the surface of the intermediate gel, and interact with polyvinyl alcohol and polyacrylamide of the outer layer of the intermediate gel to gradually form a highly hydrated cortex with a compact network structure; before the compact structure of the cortex is not completely formed, water molecules penetrate through the cortex of the middle gel to the inside, the water molecules enter the hydrogel and then are dispersed in a three-dimensional network of the polymer, hydrogen bonding is performed between the water molecules and hydrophilic functional groups on a polymer molecular chain and a nanocellulose molecular chain, the polymer molecular chain segments are loosened and stretched under the hydrogen bonding, the hydrogel network begins to swell, and the volume of the hydrogel is greatly increased. On one hand, the outer layer structure of the middle gel is gradually compact along with the extension of the soaking time, and water molecules are difficult to penetrate through the skin layer and enter the gel; on the other hand, the polymer molecular chains inside the hydrogel are also fully swelled, and finally the tendency of the swelling ratio of the hydrogel to increase is slowed down; at the end of swelling, the elastic contractive force of the polymer molecular chains will cause the three-dimensional network to contract, eventually reaching a swelling equilibrium.
In some alternative examples, the intermediate gel is immersed in an ethanol aqueous solution of sodium silicate at 50-60 ℃, for example, 50 ℃, 51 ℃, 52 ℃, 53 ℃, 54 ℃, 55 ℃, 56 ℃, 57 ℃, 58 ℃, 59 ℃, or 60 ℃, but not limited to the recited values, and other non-recited values within the range of values are equally applicable.
The invention particularly limits the soaking temperature of the intermediate gel to 50-60 ℃, can promote salting-out effect in the temperature range, enables more hydroxyl functional groups to be exposed and interacted, and is favorable for forming hydrogen bonds among the hydroxyl functional groups in the gel system; when the soaking temperature exceeds 60 ℃, the mechanical properties of the hydrogel are reduced, because the soaking temperature is too high, the brittle network in the hydrogel is increased to a critical state, and the mechanical properties of the hydrogel are reduced.
As a preferable technical scheme of the invention, in the step (III), indocyanine green is respectively prepared with the concentration of 10 - 1 mol/L、10 -2 mol/L、10 -3 mol/L、10 -4 mol/L、10 -5 mol/L and 10 -6 6 groups of hydrogels with different mol/L contents.
In some alternative examples, the frozen ambient temperature is-50 to-20 ℃, such as-50 ℃, -48 ℃, -46 ℃, -42 ℃, -40 ℃, -38 ℃, -36 ℃, -34 ℃, -32 ℃, -30 ℃, -28 ℃, -26 ℃, -24 ℃, -22 ℃, or-20 ℃, but not limited to the recited values, and other non-recited values within the range of values are equally applicable.
In some alternative examples, the freezing time is 8-12 h, for example, 8.0h, 8.5h, 9.0h, 9.5h, 10.0h, 10.5h, 11.0h, 11.5h or 12.0h, but not limited to the recited values, and other non-recited values within the range are equally applicable.
In some alternative examples, the thawing time is 4-7 h, for example, but not limited to, the recited values, and other non-recited values within the range are equally applicable.
In some alternative examples, the freezing and thawing may be repeated 3-7 times, for example, 3 times, 4 times, 5 times, 6 times, or 7 times, but is not limited to the recited values, and other non-recited values within the range are equally applicable.
With the increase of the cycle times of freezing and thawing, the equilibrium swelling ratio of the hydrogel is gradually increased, and when the cycle times reach 7 times, the tendency of the equilibrium swelling ratio of the hydrogel to increase is slowed down, which indicates that the hydrogel at the moment has formed a perfect network structure. After the polyvinyl alcohol molecular chain and the polyacrylamide molecular chain are frozen, hydroxyl groups in the molecular chain and among the molecular chains are contacted to form a crosslinking node. The polyvinyl alcohol molecular chains and the acrylamide molecular chains which are not crosslinked still have certain movement capacity after thawing, so that the hydroxyl groups which are contacted with each other form new crosslinking nodes after being frozen again, therefore, as the crosslinking density of the polyvinyl alcohol and the polyacrylamide is increased, the hydrogen bond action between the polyvinyl alcohol molecular chains and between the chains is enhanced, the polyvinyl alcohol molecular chains and the sodium alginate molecular chains jointly form a denser first semi-interpenetrating gel network, the polyacrylamide molecular chains and the sodium alginate molecular chains jointly form a denser second semi-interpenetrating gel network, the capability of the hydrogel for resisting external force action is enhanced due to the regular crosslinking structure, and finally, the tensile strength and the elongation at break of the hydrogel are improved. After the number of circulation times reaches 7 times, the number of crosslinking points of the polyvinyl alcohol molecular chain and the number of crosslinking points of the polyacrylamide molecular chain are basically fixed, the mobility of the molecular chain is weakened, and therefore the increase of the number of circulation times is not obvious for the balanced swelling ratio of the hydrogel. Meanwhile, as the number of freeze thawing cycles increases, the density of physical crosslinking points increases, the combination of polymer molecular chains is more compact, the pores of the formed gel network become smaller, the water content which can be contained in the pores decreases, and the swelling degree of the hydrogel decreases.
In a second aspect, the invention provides an indocyanine green hydrogel fluorescence calibration plate, which is prepared by the preparation method in the first aspect.
In a third aspect, the invention provides an application of the indocyanine green hydrogel fluorescence calibration plate in the second aspect, wherein the indocyanine green hydrogel fluorescence calibration plate is used for optical surgical navigation.
The invention provides a preparation method of an indocyanine green hydrogel fluorescence calibration plate, which specifically comprises the following steps:
(1) Dissolving polyvinyl alcohol in deionized water, heating the deionized water to 80-90 ℃, mixing and stirring for 10-30 min until the polyvinyl alcohol is completely dissolved, and obtaining a polyvinyl alcohol solution with the concentration of 10-20 g/mL; dissolving sodium alginate in a polyvinyl alcohol solution, wherein the mass ratio of the sodium alginate to the polyvinyl alcohol is 1 (0.1-0.3), and mixing and stirring for 1-5 hours to obtain a mixed solution;
(2) Dispersing acrylamide in the mixed solution obtained in the step (1), wherein the mass ratio of the acrylamide to the polyvinyl alcohol is (0.3-0.5): 1, heating the mixed solution to 40-50 ℃, and mixing and stirring for 1-5 hours until the acrylamide is completely dissolved; maintaining the temperature of the mixed solution unchanged and continuously stirring, adding a nano cellulose suspension with the mass fraction of 1.5-3wt% into the mixed solution in the stirring process, adding 15-20 mL of the nano cellulose suspension into each gram of polyvinyl alcohol, and continuously stirring for 0.5-1.5 h to obtain a precursor solution;
(3) Adding an initiator and a cross-linking agent into the precursor solution obtained in the step (2), wherein the addition amount of the initiator is 2-5wt% of the mass of the acrylamide, and the addition amount of the cross-linking agent is 3-10wt% of the mass of the acrylamide, and uniformly mixing and carrying out a cross-linking reaction to obtain a hydrogel solution;
(4) Adding indocyanine green into the hydrogel solution obtained in the step (3), mechanically stirring for 1-3 hours at a rotating speed of 60-120 rpm, and then ultrasonically removing bubbles from the hydrogel solution for 10-20 minutes by using ultrasonic waves of 3-5 kW to obtain a mixed gel solution; the mixed gel solution is frozen for 4 to 6 hours at the low temperature of-20 to-10 ℃ until the mixed gel solution is completely solidified, and then the mixed gel solution is thawed for 3 to 5 hours at room temperature, so that intermediate gel is obtained;
(5) Soaking the intermediate gel obtained in the step (4) in an ethanol water solution of sodium silicate at 50-60 ℃, wherein the mass fraction of sodium silicate in the ethanol water solution of sodium silicate is 30-40 wt%, the volume ratio of ethanol to water is 1 (2-3), and taking out and cleaning after soaking the intermediate gel for 1-5 h to obtain hydrogel;
(6) Preparing indocyanine green according to the operation steps of the step (4) and the step (5)Is at a concentration of 10 -1 mol/L、10 -2 mol/L、10 -3 mol/L、10 -4 mol/L、10 -5 mol/L and 10 -6 6 groups of hydrogels with different mol/L contents are respectively injected into independent sample tubes, the sample tubes are fixed in a porous plate, the porous plate is frozen for 8-12 hours in a low-temperature environment of-50 to-20 ℃, then the porous plate is thawed for 4-7 hours at room temperature, and the freezing and the thawing are repeated for 3-7 times, so that the indocyanine green hydrogel fluorescent calibration plate is obtained.
Compared with the prior art, the invention has the beneficial effects that:
the sodium alginate has excellent biocompatibility and water absorption and moisture retention, and the raw materials are wide in source, safe, nontoxic and degradable, and have wider and wider application in the aspect of biological materials. However, sodium alginate hydrogel has the defects of poor gel controllability and low mechanical strength, and when the sodium alginate hydrogel is used alone, the practical application requirements of people on the hydrogel are often difficult to meet, so that the application range of the sodium alginate hydrogel is greatly limited. According to the invention, polyvinyl alcohol and sodium alginate are compounded through an interpenetrating network technology, sodium alginate molecules enter a polyvinyl alcohol network and are physically entangled with the polyvinyl alcohol molecules, so that the cross-linking point density of the polyvinyl alcohol hydrogel is destroyed, and a first semi-interpenetrating gel network is formed.
The acrylamide monomer is subjected to thermal initiation free radical polymerization under the action of an initiator and a cross-linking agent to form a covalent cross-linked polyacrylamide network structure, linear macromolecules of sodium alginate are inserted into the covalent cross-linked polyacrylamide network structure to form a second semi-interpenetrating gel network, hydrogen bonds are formed between amino groups of polyacrylamide and hydroxyl groups of sodium alginate, intermolecular acting force between polyacrylamide molecules and sodium alginate molecules is enhanced, and therefore mechanical properties of the second semi-interpenetrating gel network are improved.
According to the invention, the polyvinyl alcohol/sodium alginate is adopted as a first semi-interpenetrating gel network, the polyacrylamide/sodium alginate is adopted as a second semi-interpenetrating gel network, a semi-interpenetrating double-network gel structure consisting of the first semi-interpenetrating gel network and the second semi-interpenetrating gel network is formed, a hydrogen bond between a polyvinyl alcohol molecular chain and a polyacrylamide molecular chain in the double-network hydrogel is adopted as a sacrificial bond, so that the external load can be effectively resisted, and the hydrogel can still quickly recover after repeated stretching or loading.
According to the invention, nanocellulose is added into a semi-interpenetrating double-network gel system of sodium alginate/polyvinyl alcohol/acrylamide, so that the indocyanine green hydrogel fluorescent calibration plate which is soft in texture, can keep a certain shape and is stable for a long time is prepared. According to the invention, the nanocellulose, the polyvinyl alcohol and the polyacrylamide are subjected to physical crosslinking, the nanocellulose can be used as a polymer reinforced phase, a large number of amino groups exist on a polyacrylamide molecular chain, a large number of hydroxyl groups exist on a polyvinyl alcohol molecular chain, and hydrogel can be formed through physical or chemical crosslinking. The surface of the nanocellulose contains a large number of hydroxyl groups, has good dispersibility in water-soluble polymers, can be combined with hydroxyl groups on a polyvinyl alcohol molecular chain and amino groups on a polyacrylamide molecular chain to form firm hydrogen bonds, and plays a role in nano reinforcement.
The invention combines freeze thawing cycle and sodium silicate salting out to prepare the hydrogel with compact cortex and porous inner layer. When the intermediate gel is soaked in the ethanol aqueous solution of sodium silicate for a period of time, salting-out effect and polarization effect can occur between the sodium silicate and the sodium alginate/polyvinyl alcohol/acrylamide gel system, under the effect of the salting-out effect, the sodium alginate/polyvinyl alcohol/acrylamide gel system is dehydrated, and in the dehydration process, the gel system forms a microcrystalline structure formed by orderly stacked hydrogen bonds. Under the effect of polarization effect, the alkali sodium silicate can enhance the interaction of hydroxyl functional groups in a sodium alginate/polyvinyl alcohol/acrylamide gel system by in-situ doping, and ethanol in the solution is deprotonated in an alkali environment, so that the hydroxyl functional groups obtain polarization enhancement effect, and the dipole-dipole interaction is shown, thereby enhancing the stability of microcrystalline tissues. By virtue of salting-out effect and polarization effect between sodium silicate and intermediate gel, strong aggregation of polymer chains on the surface of the intermediate gel and formation of microcrystals can be rapidly initiated, and a more compact and stable skin layer with a directional porous network structure is obtained, on one hand, the formation of the compact skin layer can be used as a protective barrier of indocyanine green hydrogel, so that the stability of indocyanine green hydrogel in different solvent environments is improved; on the other hand, the cortex has a compact network structure, so that the mechanical property of the hydrogel is greatly improved. When the compact cortex is formed, the penetration effect of the ethanol aqueous solution of sodium silicate on the gel is gradually weakened, and silicate is difficult to continuously penetrate into the middle gel, so that the obtained hydrogel has a porous semi-interpenetrating double-network gel structure.
The solvent of the coagulation bath adopted by the invention is ethanol water solution, and the ethanol can effectively control the swelling degree of the hydrogel in the ionic crosslinking process, and has no other adverse effects on the ionic crosslinking process. The synergistic effect of sodium silicate and ethanol ensures that the porous network structure of the formed hydrogel intermediate layer is more uniform and regular, the network pore diameter is reduced, the pore density is increased, and the mechanical property is greatly improved. The porous network structure with uniform crosslinking provides a firm structural foundation for the excellent water absorption and moisture retention of the hydrogel, and can also endow the hydrogel with good mechanical elasticity.
According to the invention, after indocyanine green is added into the hydrogel, the hydrogel-based indocyanine green fluorescent calibration plate is prepared through freeze thawing cycle curing molding, the hydrogel-based indocyanine green has a fixed shape, the hydrogel-based indocyanine green fluorescent calibration plate prepared by the preparation method provided by the invention does not influence the fluorescent property of indocyanine green, and the stability of indocyanine green in a hydrogel system can be greatly improved, photobleaching and degradation are not easy to occur, so that the fluorescent intensity of the fluorescent calibration plate which is stable for a long time is maintained, and convenience is provided for detecting the fluorescent function and sensitivity of an optical operation navigation system.
Drawings
FIG. 1 is a flow chart of the preparation process of indocyanine green hydrogel fluorescent calibration plates provided in examples 1-5 and comparative examples 1-8;
FIG. 2 is an optical image of the hydrogel prepared in example 1 of the present invention;
FIG. 3 is a scanning electron microscope image of the cortex of the hydrogel prepared in example 1 of the present invention;
FIG. 4 is a scanning electron microscope image of an intermediate layer of the hydrogel prepared in example 1 of the present invention at a scale of 10 μm;
FIG. 5 is a scanning electron microscope image of an intermediate layer of the hydrogel prepared in example 1 of the present invention at a scale of 5. Mu.m.
Detailed Description
The technical scheme of the invention is described in detail below with reference to specific embodiments and attached drawings. The examples described herein are specific embodiments of the present invention for illustrating the concept of the present invention; the description is intended to be illustrative and exemplary in nature and should not be construed as limiting the scope of the invention in its aspects. In addition to the embodiments described herein, those skilled in the art can adopt other obvious solutions based on the disclosure of the claims of the present application and the specification thereof, including those adopting any obvious substitutions and modifications to the embodiments described herein.
The information on the parameters of the manufacturers, product brands, etc. of the main chemicals used in examples 1 to 5 and comparative examples 1 to 8 are as follows:
polyvinyl alcohol: PVA205, kaiyin chemical Co., ltd., shanghai;
sodium alginate: m29284, michelveter biochemical technologies, inc. Shanghai;
acrylamide: m26842, michelveter biochemical technologies, inc. Shanghai;
nanocellulose: the solid content is more than or equal to 2 weight percent, and the northern century (Jiangsu) cellulose materials is available from the company Limited;
nanocellulose suspension: mixing commercially available nanocellulose and deionized water in proportion, dispersing, uniformly stirring, and preparing nanocellulose suspension with different concentrations;
ammonium persulfate: m33145, shanghai Michael Biochemical technologies Co., ltd;
tetramethyl ethylenediamine: m02049, michelveter biochemical technologies, inc. Shanghai;
potassium persulfate: m26049, michelveter biochemical technologies, inc. Shanghai;
n, N' -methylenebisacrylamide: m71555, michelveter biochemical technologies, inc. Shanghai;
epichlorohydrin: m32070, michelveter biochemical technologies, inc. Shanghai;
glutaraldehyde: m83903, michelveter biochemical technologies, inc. Shanghai;
borax: m69848, michelveter biochemical technologies, inc. Shanghai;
Polyethylene glycol: m12024, shanghai Michael Biochemical technologies Co., ltd;
indocyanine green: KM0146, beijing berlaibo technologies limited;
sodium silicate: JR1687, henan brocade New Material Co.
Example 1
The embodiment provides a preparation method of an indocyanine green hydrogel fluorescence calibration plate, as shown in fig. 1, which specifically comprises the following steps:
(1) Dissolving polyvinyl alcohol in deionized water, heating the deionized water to 80 ℃, mixing and stirring for 30min until the polyvinyl alcohol is completely dissolved, and obtaining a polyvinyl alcohol solution with the concentration of 10 g/mL; dissolving sodium alginate in a polyvinyl alcohol solution, mixing and stirring for 1h to obtain a mixed solution, wherein the mass ratio of the sodium alginate to the polyvinyl alcohol is 1:0.1;
(2) Dispersing acrylamide in the mixed solution obtained in the step (1), wherein the mass ratio of the acrylamide to the polyvinyl alcohol is 0.3:1, heating the mixed solution to 40 ℃, mixing and stirring for 5 hours until the acrylamide is completely dissolved; maintaining the temperature of the mixed solution unchanged and continuously stirring, adding nano cellulose suspension with the mass fraction of 1.5wt% into the mixed solution in the stirring process, adding 20mL of nano cellulose suspension into each gram of polyvinyl alcohol, and continuously stirring for 0.5h to obtain a precursor solution;
(3) Adding ammonium persulfate and N, N '-methylene bisacrylamide into the precursor solution obtained in the step (2), wherein the addition amount of the ammonium persulfate is 2wt% of the mass of the acrylamide, and the addition amount of the N, N' -methylene bisacrylamide is 3wt% of the mass of the acrylamide, and uniformly mixing and carrying out a crosslinking reaction to obtain a hydrogel solution;
(4) Adding indocyanine green into the hydrogel solution obtained in the step (3), mechanically stirring for 3 hours at a rotating speed of 60rpm, and then ultrasonically removing bubbles from the hydrogel solution for 20 minutes by using ultrasonic waves of 3kW to obtain a mixed gel solution; freezing the mixed gel solution in a low-temperature environment of-10 ℃ for 6 hours until the mixed gel solution is completely solidified, and then thawing the mixed gel solution at room temperature for 5 hours to obtain intermediate gel;
(5) Soaking the intermediate gel obtained in the step (4) in an ethanol water solution of sodium silicate at 50 ℃, wherein the mass fraction of sodium silicate in the ethanol water solution of sodium silicate is 30wt%, the volume ratio of ethanol to water is 1:2, and taking out and cleaning the intermediate gel after soaking for 5 hours to obtain hydrogel;
(6) Preparing indocyanine green with concentration of 10 according to the operation steps of the step (4) and the step (5) -1 mol/L、10 -2 mol/L、10 -3 mol/L、10 -4 mol/L、10 -5 mol/L and 10 -6 6 groups of hydrogels with different contents in mol/L are respectively injected into independent sample tubes, the sample tubes are fixed in a porous plate, the porous plate is frozen for 12 hours in a low-temperature environment of-20 ℃, then the porous plate is thawed for 7 hours at room temperature, and the indocyanine green hydrogel fluorescent calibration plate is obtained by repeating the freezing and thawing for 3 times.
Fig. 2 is an optical image of the hydrogel prepared in this example, and it can be seen that it forms a layered structure, and a skin layer of a dense structure and an intermediate layer of a porous structure are present.
Fig. 3 is a scanning electron microscope image of the hydrogel skin prepared in this example, and it can be seen that the hydrogel skin has a compact and flat structure and no pores.
Fig. 4 is a scanning electron microscope image of the hydrogel intermediate layer at a 10 μm scale, and it can be seen that the hydrogel intermediate layer has a porous structure and uniform pore size, which indicates that the polyvinyl alcohol molecular chains, the polyacrylamide molecular chains and the nanocellulose form strong bonding through hydrogen bonds, covalent bonds or intermolecular forces.
FIG. 5 is a scanning electron microscope image of the middle layer of the hydrogel at a scale of 5 μm, showing nanocellulose dispersed in the porous structure of the hydrogel (circles), the diameter of these fibres being below 100nm and the bond with the porous structure being relatively tight.
Example 2
The embodiment provides a preparation method of an indocyanine green hydrogel fluorescence calibration plate, as shown in fig. 1, which specifically comprises the following steps:
(1) Dissolving polyvinyl alcohol in deionized water, heating the deionized water to 82 ℃, mixing and stirring for 25min until the polyvinyl alcohol is completely dissolved, and obtaining a polyvinyl alcohol solution with the concentration of 12 g/mL; dissolving sodium alginate in a polyvinyl alcohol solution, mixing and stirring for 2 hours to obtain a mixed solution, wherein the mass ratio of the sodium alginate to the polyvinyl alcohol is 1:0.15;
(2) Dispersing acrylamide in the mixed solution obtained in the step (1), wherein the mass ratio of the acrylamide to the polyvinyl alcohol is 0.35:1, heating the mixed solution to 42 ℃, mixing and stirring for 4 hours until the acrylamide is completely dissolved; maintaining the temperature of the mixed solution unchanged and continuously stirring, adding nano cellulose suspension with the mass fraction of 1.8wt% into the mixed solution in the stirring process, adding 18mL of nano cellulose suspension into each gram of polyvinyl alcohol, and continuously stirring for 0.8h to obtain a precursor solution;
(3) Adding ammonium persulfate and epoxy chloropropane into the precursor solution obtained in the step (2), wherein the addition amount of the ammonium persulfate is 3wt% of the mass of the acrylamide, and the addition amount of the epoxy chloropropane is 5wt% of the mass of the acrylamide, and uniformly mixing and carrying out a crosslinking reaction to obtain a hydrogel solution;
(4) Adding indocyanine green into the hydrogel solution obtained in the step (3), mechanically stirring for 2.5 hours at a rotating speed of 70rpm, and then ultrasonically removing bubbles from the hydrogel solution for 18 minutes by using ultrasonic waves of 3.5kW to obtain a mixed gel solution; freezing the mixed gel solution at-12 ℃ for 5.5 hours until the mixed gel solution is completely solidified, and then thawing the mixed gel solution at room temperature for 4.5 hours to obtain intermediate gel;
(5) Soaking the intermediate gel obtained in the step (4) in an ethanol water solution of sodium silicate at 52 ℃, wherein the mass fraction of sodium silicate in the ethanol water solution of sodium silicate is 32wt%, the volume ratio of ethanol to water is 1:2.2, and taking out and cleaning the intermediate gel after soaking for 4 hours to obtain hydrogel;
(6) Preparing indocyanine green with concentration of 10 according to the operation steps of the step (4) and the step (5) -1 mol/L、10 -2 mol/L、10 -3 mol/L、10 -4 mol/L、10 -5 mol/L and 10 -6 6 groups of hydrogels with different contents in mol/L are respectively injected into independent sample tubes, the sample tubes are fixed in a porous plate, the porous plate is frozen for 11 hours in a low-temperature environment of minus 30 ℃, then the porous plate is thawed for 6 hours at room temperature, and the indocyanine green hydrogel fluorescent calibration plate is obtained by repeated freezing and thawing for 4 times.
Example 3
The embodiment provides a preparation method of an indocyanine green hydrogel fluorescence calibration plate, as shown in fig. 1, which specifically comprises the following steps:
(1) Dissolving polyvinyl alcohol in deionized water, heating the deionized water to 85 ℃, mixing and stirring for 20min until the polyvinyl alcohol is completely dissolved, and obtaining a polyvinyl alcohol solution with the concentration of 15 g/mL; dissolving sodium alginate in a polyvinyl alcohol solution, mixing and stirring for 3 hours to obtain a mixed solution, wherein the mass ratio of the sodium alginate to the polyvinyl alcohol is 1:0.2;
(2) Dispersing acrylamide in the mixed solution obtained in the step (1), wherein the mass ratio of the acrylamide to the polyvinyl alcohol is 0.4:1, heating the mixed solution to 45 ℃, mixing and stirring for 3 hours until the acrylamide is completely dissolved; maintaining the temperature of the mixed solution unchanged and continuously stirring, adding a nano cellulose suspension with the mass fraction of 2wt% into the mixed solution in the stirring process, adding 17mL of the nano cellulose suspension into each gram of polyvinyl alcohol, and continuously stirring for 1h to obtain a precursor solution;
(3) Adding potassium persulfate and glutaraldehyde into the precursor solution obtained in the step (2), wherein the addition amount of the potassium persulfate is 3.5 weight percent of the mass of the acrylamide, and the addition amount of the glutaraldehyde is 7 weight percent of the mass of the acrylamide, and uniformly mixing and carrying out a crosslinking reaction to obtain a hydrogel solution;
(4) Adding indocyanine green into the hydrogel solution obtained in the step (3), mechanically stirring for 2 hours at a rotating speed of 80rpm, and then ultrasonically removing bubbles from the hydrogel solution for 15 minutes by using 4kW ultrasonic waves to obtain a mixed gel solution; freezing the mixed gel solution in a low-temperature environment of-15 ℃ for 5 hours until the mixed gel solution is completely solidified, and then thawing the mixed gel solution at room temperature for 4 hours to obtain intermediate gel;
(5) Soaking the intermediate gel obtained in the step (4) in an ethanol water solution of sodium silicate at 55 ℃, wherein the mass fraction of sodium silicate in the ethanol water solution of sodium silicate is 35wt%, the volume ratio of ethanol to water is 1:2.5, and taking out and cleaning the intermediate gel after soaking for 3 hours to obtain hydrogel;
(6) Preparing indocyanine green with concentration of 10 according to the operation steps of the step (4) and the step (5) -1 mol/L、10 -2 mol/L、10 -3 mol/L、10 -4 mol/L、10 -5 mol/L and 10 -6 6 groups of hydrogels with different contents in mol/L are respectively injected into independent sample tubes, the sample tubes are fixed in a porous plate, the porous plate is frozen for 10 hours in a low-temperature environment of minus 35 ℃, then the porous plate is thawed for 5.5 hours at room temperature, and the indocyanine green hydrogel fluorescent calibration plate is obtained by repeating the freezing and thawing for 5 times.
Example 4
The embodiment provides a preparation method of an indocyanine green hydrogel fluorescence calibration plate, as shown in fig. 1, which specifically comprises the following steps:
(1) Dissolving polyvinyl alcohol in deionized water, heating the deionized water to 88 ℃, mixing and stirring for 15min until the polyvinyl alcohol is completely dissolved, and obtaining a polyvinyl alcohol solution with the concentration of 18 g/mL; dissolving sodium alginate in a polyvinyl alcohol solution, mixing and stirring for 4 hours to obtain a mixed solution, wherein the mass ratio of the sodium alginate to the polyvinyl alcohol is 1:0.25;
(2) Dispersing acrylamide in the mixed solution obtained in the step (1), wherein the mass ratio of the acrylamide to the polyvinyl alcohol is 0.45:1, heating the mixed solution to 48 ℃, mixing and stirring for 2 hours until the acrylamide is completely dissolved; maintaining the temperature of the mixed solution unchanged and continuously stirring, adding 2.5wt% of nano cellulose suspension into the mixed solution in the stirring process, adding 16mL of nano cellulose suspension into each gram of polyvinyl alcohol, and continuously stirring for 1.2h to obtain a precursor solution;
(3) Adding potassium persulfate and borax into the precursor solution obtained in the step (2), wherein the addition amount of the potassium persulfate is 4wt% of the mass of the acrylamide, and the addition amount of the borax is 8wt% of the mass of the acrylamide, and uniformly mixing and carrying out a crosslinking reaction to obtain a hydrogel solution;
(4) Adding indocyanine green into the hydrogel solution obtained in the step (3), mechanically stirring for 1.5h at a rotating speed of 100rpm, and then ultrasonically removing bubbles from the hydrogel solution for 12min through ultrasonic waves of 4.5kW to obtain a mixed gel solution; freezing the mixed gel solution at-18 ℃ for 4.5 hours until the mixed gel solution is completely solidified, and then thawing the mixed gel solution at room temperature for 3.5 hours to obtain intermediate gel;
(5) Soaking the intermediate gel obtained in the step (4) in an ethanol water solution of sodium silicate at 58 ℃, wherein the mass fraction of sodium silicate in the ethanol water solution of sodium silicate is 38wt%, the volume ratio of ethanol to water is 1:2.8, and taking out and cleaning the intermediate gel after soaking for 2 hours to obtain hydrogel;
(6) Preparing indocyanine green with concentration of 10 according to the operation steps of the step (4) and the step (5) -1 mol/L、10 -2 mol/L、10 -3 mol/L、10 -4 mol/L、10 -5 mol/L and 10 -6 6 groups of hydrogels with different contents in mol/L are respectively injected into independent sample tubes, the sample tubes are fixed in a porous plate, the porous plate is frozen for 9 hours in a low-temperature environment of minus 40 ℃, then the porous plate is thawed for 5 hours at room temperature, and the indocyanine green hydrogel fluorescent calibration plate is obtained by repeated freezing and thawing for 6 times.
Example 5
The embodiment provides a preparation method of an indocyanine green hydrogel fluorescence calibration plate, as shown in fig. 1, which specifically comprises the following steps:
(1) Dissolving polyvinyl alcohol in deionized water, heating the deionized water to 90 ℃, mixing and stirring for 10min until the polyvinyl alcohol is completely dissolved, and obtaining a polyvinyl alcohol solution with the concentration of 20 g/mL; dissolving sodium alginate in a polyvinyl alcohol solution, mixing and stirring for 5 hours to obtain a mixed solution, wherein the mass ratio of the sodium alginate to the polyvinyl alcohol is 1:0.3;
(2) Dispersing acrylamide in the mixed solution obtained in the step (1), wherein the mass ratio of the acrylamide to the polyvinyl alcohol is 0.5:1, heating the mixed solution to 50 ℃, mixing and stirring for 1h until the acrylamide is completely dissolved; maintaining the temperature of the mixed solution unchanged and continuously stirring, adding 3wt% of nano cellulose suspension into the mixed solution in the stirring process, adding 15mL of nano cellulose suspension into each gram of polyvinyl alcohol, and continuously stirring for 1.5h to obtain a precursor solution;
(3) Adding tetramethyl ethylenediamine and polyethylene glycol into the precursor solution obtained in the step (2), wherein the addition amount of the tetramethyl ethylenediamine is 5wt% of the mass of the acrylamide, and the addition amount of the polyethylene glycol is 10wt% of the mass of the acrylamide, and uniformly mixing and carrying out a crosslinking reaction to obtain a hydrogel solution;
(4) Adding indocyanine green into the hydrogel solution obtained in the step (3), mechanically stirring for 1h at a rotating speed of 120rpm, and then ultrasonically removing bubbles from the hydrogel solution for 10min through ultrasonic waves of 5kW to obtain a mixed gel solution; freezing the mixed gel solution in a low-temperature environment of-20 ℃ for 4 hours until the mixed gel solution is completely solidified, and then thawing the mixed gel solution at room temperature for 3 hours to obtain intermediate gel;
(5) Soaking the intermediate gel obtained in the step (4) in an ethanol water solution of sodium silicate at 60 ℃, wherein the mass fraction of sodium silicate in the ethanol water solution of sodium silicate is 40wt%, the volume ratio of ethanol to water is 1:3, and taking out and cleaning the intermediate gel after soaking for 1h to obtain hydrogel;
(6) Preparing indocyanine green with concentration of 10 according to the operation steps of the step (4) and the step (5) -1 mol/L、10 -2 mol/L、10 -3 mol/L、10 -4 mol/L、10 -5 mol/L and 10 -6 6 groups of hydrogels with different contents in mol/L are respectively injected into independent sample tubes, the sample tubes are fixed in a porous plate, the porous plate is frozen for 8 hours in a low-temperature environment of 50 ℃ below zero, then the porous plate is thawed for 4 hours at room temperature, and the indocyanine green hydrogel fluorescent calibration plate is obtained by repeated freezing and thawing for 7 times.
Comparative example 1
The comparison example provides a preparation method of indocyanine green hydrogel fluorescent calibration plate, which is different from the embodiment 1 in that the mass ratio of sodium alginate to polyvinyl alcohol in the step (1) is adjusted to be 1:0.05, and other process parameters and operation steps are identical to those in the embodiment 1.
Comparative example 2
The comparison example provides a preparation method of indocyanine green hydrogel fluorescent calibration plate, which is different from the embodiment 1 in that the mass ratio of sodium alginate to polyvinyl alcohol in the step (1) is adjusted to be 1:0.4, and other process parameters and operation steps are identical to those in the embodiment 1.
Comparative example 3
The comparison example provides a preparation method of an indocyanine green hydrogel fluorescent calibration plate, which is different from the embodiment 1 in that the mass ratio of acrylamide to polyvinyl alcohol in the step (2) is adjusted to be 0.2:1, and other process parameters and operation steps are identical to those of the embodiment 1.
Comparative example 4
The comparative example provides a preparation method of an indocyanine green hydrogel fluorescent calibration plate, which is different from the embodiment 1 in that the mass ratio of acrylamide to polyvinyl alcohol in the step (2) is adjusted to be 0.6:1, and other process parameters and operation steps are identical to those of the embodiment 1.
Comparative example 5
The comparative example provides a preparation method of an indocyanine green hydrogel fluorescence calibration plate, which is different from the preparation method in the embodiment 1 in that 10mL of nano-cellulose suspension is correspondingly added into each gram of polyvinyl alcohol in the step (2), and other process parameters and operation steps are identical to those in the embodiment 1.
Comparative example 6
The comparative example provides a preparation method of an indocyanine green hydrogel fluorescence calibration plate, which is different from the preparation method in the embodiment 1 in that 25mL of nanocellulose suspension is correspondingly added into each gram of polyvinyl alcohol in the step (2), and other process parameters and operation steps are identical to those in the embodiment 1.
Comparative example 7
The comparative example provides a preparation method of indocyanine green hydrogel fluorescence calibration plate, which is different from example 1 in that the mass fraction of sodium silicate in the ethanol aqueous solution of sodium silicate in step (5) is adjusted to 25wt%, and other process parameters and operation steps are identical to those of example 1.
Comparative example 8
The comparative example provides a preparation method of indocyanine green hydrogel fluorescence calibration plate, which is different from example 1 in that the mass fraction of sodium silicate in the ethanol aqueous solution of sodium silicate in step (5) is adjusted to 45wt%, and other process parameters and operation steps are identical to those of example 1.
The indocyanine green hydrogel fluorescent calibration plates provided in examples 1-5 and comparative examples 1-8 were tested for equilibrium swelling ratio, tensile strength, and elongation at break, as follows:
(1) Equilibrium swelling ratio
Drying the prepared hydrogel to constant weight W 0 Swelling in deionized water, wiping clean surface water with filter paper after swelling is balanced at room temperature, and recording hydrogel mass W n . The Equilibrium Swelling Ratio (ESR) of the hydrogels was calculated using the following formula:
(2) Tensile Strength and elongation at break
The hydrogel was cut into 40mmx10mm strips and tested for stretching on a universal tooling machine at a set stretching rate of 50mm/min and the stretching was stopped until the sample broke. The Tensile Strength (TS) of the hydrogels was calculated using the following formula:
Wherein F is max A is the maximum tensile stress, and a is the cross-sectional area of the sample;
the elongation at break (E) of the hydrogel was calculated using the following formula:
wherein L is 0 And L n The initial length of the sample and the length of the sample at break, respectively.
The test results are shown in Table 1.
TABLE 1 test results for examples 1-5 and comparative examples 1-8
From the test data provided in examples 1-5, it can be seen that the hydrogel provided by the invention has excellent moisture absorption and retention properties and mechanical properties, so that stable storage of indocyanine green is realized.
As can be seen from the test data provided in example 1, comparative example 1 and comparative example 2, the addition amount of sodium alginate in comparative example 1 is too high, which results in too compact a first semi-interpenetrating gel network structure, which is unfavorable for free movement of water molecules, so that the equilibrium swelling ratio of the hydrogel is reduced, meanwhile, the mobility of molecular chains is reduced, the molecular chains cannot move freely under the action of external force, the brittleness of the hydrogel is improved, and the elongation at break is reduced; however, the sodium alginate in comparative example 2 was too low to form a perfect interpenetrating gel network structure, resulting in a decrease in the mechanical properties of the hydrogel.
As can be seen from the test data provided in example 1, comparative example 3 and comparative example 4, the addition amount of acrylamide in comparative example 3 is too low, the free radical polymerization reaction is insufficient, the acrylamide monomer is not enough to effectively crosslink, the degree of crosslinking is low, the structure of the formed second semi-interpenetrating gel network is imperfect, and the equilibrium swelling ratio and mechanical property of the hydrogel are reduced; the too high acrylamide addition in comparative example 4 results in too high crosslinking density of the second semi-interpenetrating gel network structure, resulting in a decrease in the equilibrium swelling ratio of the hydrogel, and simultaneously, a decrease in the mobility of the polyacrylamide molecular chain, resulting in a decrease in the elongation at break of the hydrogel.
As can be seen from the test data provided in example 1, comparative example 5 and comparative example 6, the addition amount of the nanocellulose suspension in comparative example 5 is too low to effectively exert the mechanical enhancement and the water absorption and moisture retention effects of nanocellulose, resulting in reduced equilibrium swelling ratio, tensile strength and elongation at break of the hydrogel; the addition amount of the nanocellulose suspension in comparative example 6 is too high, so that the viscosity of the precursor solution is too high, the fluidity is poor, the dispersion uniformity of the subsequent initiator and the crosslinking agent in the precursor solution is affected, the crosslinking reaction of the acrylamide is further affected, the second semi-interpenetrating gel network structure formed by the polyacrylamide is imperfect, and finally the mechanical property of the hydrogel is reduced.
As can be seen from the test data provided in example 1, comparative example 7 and comparative example 8, the concentration of sodium silicate in the aqueous ethanol solution of sodium silicate in comparative example 7 is too low, resulting in a smaller thickness of the skin layer and a lower degree of densification, which ultimately affects the mechanical properties of the hydrogels; in comparative example 8, the concentration of sodium silicate in the aqueous ethanol solution of sodium silicate is too high, the permeation of sodium silicate to the hydrogel is weakened, and meanwhile, the sodium silicate cannot continuously permeate into the hydrogel due to the fact that the cortex is too compact, so that the thickness of the cortex cannot be continuously increased, and the improvement of the mechanical property of the hydrogel is not obvious.
The applicant declares that the above is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and it should be apparent to those skilled in the art that any changes or substitutions that are easily conceivable within the technical scope of the present invention disclosed by the present invention fall within the scope of the present invention and the disclosure.
Claims (10)
1. The preparation method of the indocyanine green hydrogel fluorescent calibration plate is characterized by comprising the following steps of:
dissolving sodium alginate in a polyvinyl alcohol solution, and uniformly mixing to obtain a mixed solution; sequentially adding acrylamide and nanocellulose suspension into the mixed solution, and uniformly mixing to obtain a precursor solution; adding an initiator and a cross-linking agent into the precursor solution, uniformly mixing and carrying out a cross-linking reaction to obtain a hydrogel solution;
(II) adding indocyanine green into the hydrogel solution obtained in the step (I), uniformly mixing, and then performing ultrasonic defoaming to obtain a mixed gel solution; freezing the mixed gel solution at low temperature until the mixed gel solution is completely solidified, and then thawing the mixed gel solution at room temperature to obtain intermediate gel; soaking the intermediate gel in an ethanol water solution of sodium silicate, and taking out and cleaning after soaking to obtain hydrogel;
And (III) preparing a plurality of groups of hydrogels containing indocyanine green with different concentrations, respectively injecting the hydrogels into independent sample tubes, fixing the sample tubes in a porous plate, freezing the porous plate in a low-temperature environment, then thawing the porous plate at room temperature, and repeatedly freezing and thawing the porous plate at least three times to obtain the indocyanine green hydrogel fluorescence calibration plate.
2. The method for preparing the indocyanine green hydrogel fluorescent calibration plate according to claim 1, wherein in the step (I), the polyvinyl alcohol solution is prepared by the following method:
dissolving the polyvinyl alcohol in deionized water, heating the deionized water, mixing and stirring until the polyvinyl alcohol is completely dissolved, and obtaining the polyvinyl alcohol solution;
wherein, the deionized water is heated to 80-90 ℃;
the mixing and stirring time of the polyvinyl alcohol in the deionized water is 10-30 min;
the concentration of the polyvinyl alcohol in the polyvinyl alcohol solution is 10-20 g/mL;
the mass ratio of the sodium alginate to the polyvinyl alcohol in the polyvinyl alcohol solution is 1 (0.1-0.3);
and the time for mixing and stirring the sodium alginate in the polyvinyl alcohol solution is 1-5 h.
3. The method for preparing the indocyanine green hydrogel fluorescent calibration plate according to claim 1, wherein in the step (i), the precursor solution is prepared by the following method:
Dispersing acrylamide in a mixed solution, heating, mixing and stirring the mixed solution until the acrylamide is completely dissolved, maintaining the temperature of the mixed solution unchanged and continuously stirring, simultaneously adding the nanocellulose suspension into the mixed solution, and continuously stirring to obtain the precursor solution;
wherein the mass ratio of the acrylamide to the polyvinyl alcohol is (0.3-0.5): 1;
heating the mixed solution to 40-50 ℃;
adding acrylamide, and stirring for 1-5 hours until the acrylamide is completely dissolved;
the mass fraction of the nanocellulose suspension is 1.5-3wt%;
the addition amount of the nanocellulose suspension is as follows: adding 15-20 mL of nanocellulose suspension liquid into each gram of polyvinyl alcohol correspondingly;
and (5) continuously stirring for 0.5-1.5 h after adding the nanocellulose suspension.
4. The method for preparing the indocyanine green hydrogel fluorescent calibration plate according to claim 1, wherein in the step (I), the initiator is any one or a combination of at least two of ammonium persulfate, tetramethyl ethylenediamine and potassium persulfate;
the addition amount of the initiator is 2-5wt% of the mass of the acrylamide;
the cross-linking agent is any one or the combination of at least two of N, N' -methylene bisacrylamide, epichlorohydrin, glutaraldehyde, borax and polyethylene glycol;
The addition amount of the cross-linking agent is 3-10wt% of the mass of the acrylamide.
5. The method for preparing an indocyanine green hydrogel fluorescence calibration plate according to claim 1, wherein in the step (ii), the indocyanine green and the hydrogel solution are mixed by mechanical stirring;
the mechanical stirring time is 1-3 hours;
the rotating speed of the mechanical stirring is 60-120 rpm;
the ultrasonic power adopted by the ultrasonic defoaming is 3-5 kW;
the ultrasonic defoaming time is 10-20 min.
6. The method for preparing indocyanine green hydrogel fluorescent calibration plate according to claim 1, wherein in the step (ii), the low-temperature freezing temperature of the mixed gel solution is-20 to-10 ℃;
the low-temperature freezing time of the mixed gel solution is 4-6 hours;
the thawing time of the mixed gel solution at room temperature is 3-5 h.
7. The method for preparing indocyanine green hydrogel fluorescent calibration plates according to claim 1, wherein in the step (II), the mass fraction of sodium silicate in the ethanol aqueous solution of sodium silicate is 30-40 wt%;
in the ethanol water solution of sodium silicate, the volume ratio of ethanol to water is 1 (2-3);
the soaking time of the intermediate gel in the ethanol water solution of the sodium silicate is 1-5 h;
The intermediate gel is soaked in an ethanol water solution of sodium silicate at 50-60 ℃.
8. The method for preparing indocyanine green hydrogel fluorescent calibration plate according to claim 1, wherein in the step (III), indocyanine green is prepared respectively with a concentration of 10 -1 mol/L、10 -2 mol/L、10 -3 mol/L、10 -4 mol/L、10 -5 mol/L and 10 -6 6 groups of hydrogels with different contents in mol/L;
the freezing environment temperature is-50 to-20 ℃;
the freezing time is 8-12 hours;
the thawing time is 4-7 hours;
the freezing and thawing are repeated for 3-7 times.
9. An indocyanine green hydrogel fluorescence calibration plate, which is characterized in that the indocyanine green hydrogel fluorescence calibration plate is prepared by the preparation method of any one of claims 1 to 8.
10. Use of the indocyanine green hydrogel fluorescence calibration plate according to claim 9 for optical surgical navigation.
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