CN109761843B - Bridging molecule for bonding metal material and hydrogel and preparation method and application thereof - Google Patents
Bridging molecule for bonding metal material and hydrogel and preparation method and application thereof Download PDFInfo
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- CN109761843B CN109761843B CN201910042373.8A CN201910042373A CN109761843B CN 109761843 B CN109761843 B CN 109761843B CN 201910042373 A CN201910042373 A CN 201910042373A CN 109761843 B CN109761843 B CN 109761843B
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Abstract
The invention belongs to the field of organic functional molecule synthesis, and discloses a bridging molecule for bonding a metal material and hydrogel, and a preparation method and application thereof. The invention introduces functional groups which can act with the metal surface and the hydrogel into bridging molecules, takes the functional groups as molecular interface ties, accesses chemical anchor points on the metal surface by surface modification methods such as in-situ spraying, dip coating and the like, and leads two end group functional groups of the bridging molecules to be respectively bonded with the hydrogel and the metal surface by in-situ polymerization reaction, thereby achieving high-strength bonding between the two. When the bridging molecule containing the responsive group is used, the bridging molecule can be quickly disconnected through external stimulus response on the basis of realizing high-strength adhesion, and then the effect of separation on demand is achieved. The bridging molecule of the invention has simple synthesis and good repeatability, can be prepared in an enlarged way, has convenient and efficient whole surface treatment and bonding process, is expected to be widely applied to the relevant fields of biomedicine, and has higher clinical application value.
Description
Technical Field
The invention belongs to the field of organic functional molecule synthesis, and particularly relates to a bridging molecule for bonding a metal material and hydrogel, and a preparation method and application thereof.
Background
With the development of modern medicine, artificial implantable medical devices are receiving great attention and attention from the industry. However, the high structural complexity of human tissues and organs has made single structure and composition artificial repair devices unable to meet the actual demands of diversification in the clinic. Based on the above, a novel bionic implantable medical device is developed by combining a flexible hydrogel material and a rigid medical alloy material, so that a feasible new idea is provided.
At present, although people still cannot imitate the complex structure of a biological system technically, the development of a new generation of medical implantable instruments with bionic structures and functions still has important basic research significance and wide clinical application prospects. Hydrogel materials generally refer to hydrophilic polymers with three-dimensional network-like cross-linked structures, and can better adapt to biochemical and mechanical environments of human tissues due to the characteristics of higher water content, adjustable mechanical properties, better biocompatibility, degradability and the like; and functional groups with biological activity can be introduced through proper chemical modification, so that the regulation and control of various cell behaviors are realized. Therefore, hydrogel materials have been widely used to replace and repair soft tissue organs in the human body. On the other hand, medical metal/alloy materials, such as titanium alloys and magnesium alloys, are used for supporting, protecting, and repairing and replacing hard tissues due to their high mechanical strength and fatigue resistance. However, how to achieve high-strength adhesion between hydrogel and rigid medical metal material is a difficulty and innovation point of current related field research.
In addition, in practical application, for example: the complexity of repairing tissues and physiological environment or the need of temporarily changing the position of hydrogel on medical metal, the need of replacing the hydrogel after implanting materials, and the like, and the need of conveniently and quickly separating the hydrogel material from the medical metal material, therefore, how to realize the quick separation between the hydrogel and the rigid medical metal material is also a hotspot of research in the related field at present.
Disclosure of Invention
To overcome the above-mentioned drawbacks and deficiencies of the prior art, it is a primary object of the present invention to provide a bridging molecule for bonding a metal material and a hydrogel.
It is another object of the present invention to provide a method for preparing the bridged molecule for bonding a metallic material and a hydrogel.
The invention further aims to provide application of the bridging molecule for bonding the metal material and the hydrogel in realizing high-strength bonding of the hydrogel and the metal material interface, in particular application in preparing a bionic implantable medical device for combining a flexible hydrogel material and a rigid medical metal material.
The purpose of the invention is realized by the following scheme:
a bridging molecule for bonding a metallic material to a hydrogel, having the general structural formula:
wherein R is1Represents a group containing at least one functional group that can crosslink the hydrogel network, wherein the functional group that crosslinks the hydrogel network includes, but is not limited to, alkenyl, alkynyl, amino, catechol, methacrylate, methacrylamide, acrylate, acrylamide, thiol, and hydroxyl; r1Preferably a methacrylamide group, a methacrylate group or an acrylate group;
R2represents a group containing at least one functional group that can be bonded to the metallic material, wherein the functional group bonded to the metallic material includes, but is not limited to, carboxylate, catechol, phosphate, pyridine-based nitrogen-containing heterocycles, and lipoic acid; preferably a carboxylate or lipoic acid group;
X1-X2represents a dynamic chemical bond, a simple linking group, or a linking group containing at least one stimuli-responsive group, wherein a simple linking group includes, but is not limited to, at least two combinations of one or more linking groups from the group consisting of alkyl groups, alkenyl groups, ketone groups, and ether groups; the stimulus-responsive group includes, but is not limited to, a pH-sensitive group, a temperature-sensitive group, a redox-sensitive group and a photo-responsive group, and when the bridging molecule contains a stimulus-responsive functional group, the bridging molecule acts on the interface of the metal material and the hydrogel material, so that the high-strength bonding of the metal material and the hydrogel material and the separation required under the specific stimulus from the outside can be realized.
Preferably, the pH sensitive group includes, but is not limited to, tertiary amines, secondary amines, sulfonic acid groups; such temperature sensitive groups include, but are not limited to, amide groups and ethers; the redox-sensitive groups include, but are not limited to, disulfide groups, amino groups, alkynyl groups, and alkenyl groups; the photoresponsive group includes but is not limited to chlorophyllin, aromatic azide group and o-nitrobenzyl alcohol derivative.
Preferably, the bridging molecule has a structural formula that is one of the following structural formulas:
in the above preferred structural formula of the bridging molecule, the functional group that crosslinks with the hydrogel network is a methacrylamide group, a methacrylate group, or an acrylate group; the groups of the functional groups bonded to the metal are carboxylate or lipoic acid groups, respectively, while the bridging molecule 2 contains a disulfide group as a redox-sensitive group.
A method for preparing the bridging molecule for bonding the metal material and the hydrogel comprises the following steps:
in the case of the bridged molecule 1, the preparation method thereof comprises the following steps: dissolving 12-aminododecanoic acid and triethylamine in an organic solvent, adding methacrylic anhydride, stirring and reacting to obtain a bridging molecule 1 after the reaction is finished, wherein the reaction formula is as follows:
in the preparation of the bridged molecule 1:
the dosage ratio of the 12-aminododecanoic acid to the methacrylic anhydride to the triethylamine is 1-10.0 g: 1-20 mL: 1-50 mL; the dosage of the organic solvent is such that 20-300 mL of the organic solvent is correspondingly added into every 1-10 g of 12-aminododecanoic acid;
the organic solvent is at least one of tetrahydrofuran, dichloromethane, chloroform and acetone;
the stirring reaction is carried out in an ice water bath for 4-36 hours; after the stirring reaction is finished, the method also comprises the step of removing impurities by using deionized water for extraction.
In the case of the bridged molecule 2, the preparation method comprises the following steps: dissolving dithiodiglycol diacetic acid in acetic anhydride for reaction to obtain annular dithioic anhydride, dissolving the obtained annular dithioic anhydride and hydroxyethyl methacrylate in an organic solvent, and stirring for reaction to obtain bridging molecules 2, wherein the reaction formula is shown as follows:
in the preparation of the bridged molecule 2:
the mass volume ratio of the dithiodiglycol diacetic acid to the acetic anhydride is 0.1-2.0 g: 1.0-20 mL; the dosage of the organic solvent is such that 10-30 mL of organic solvent is correspondingly added to every 0.2-2.0 g of hydroxyethyl methacrylate; the temperature for dissolving the dithiodiglycol diacetic acid in the acetic anhydride for reaction is 0-40 ℃, and the reaction time is 4-24 h;
the organic solvent is at least one of chloroform, N-dimethylformamide, acetone, tetrahydrofuran, isopropanol, N-dimethylacetamide and dichloromethane, and dichloromethane or tetrahydrofuran is preferred;
the dosage of the cyclic dithioic anhydride and the hydroxyethyl methacrylate meets the requirement that the mass ratio of the raw materials of the cyclic dithioic anhydride, namely the dithioic diglycol diacetate and the hydroxyethyl methacrylate is 0.1-2.0: 0.2 to 2.0; the dosage of the organic solvent is such that 10-30 mL of organic solvent is correspondingly added to every 0.2-2.0 g of hydroxyethyl methacrylate;
the stirring reaction is carried out for 12-72 h in an ice-water bath environment at a rotating speed of 100-1000 rpm, and the method further comprises the following steps of adopting a gel chromatographic column to obtain a mixture with a volume ratio of petroleum ether to ethyl acetate (0.5-4): 1 purifying under the action of mixed solvent.
In the case of the bridging molecule 3, the preparation method thereof comprises the following steps: adding lipoic acid, 4-dimethylaminopyridine, dicyclohexylcarbodiimide and hydroxyethyl acrylate into an organic solvent under ice bath, stirring for reaction, and obtaining a bridging molecule 3 after the reaction is finished, wherein the reaction formula is as follows:
in the method of preparation of the bridging molecule 3:
the dosage ratio of the lipoic acid, the 4-dimethylaminopyridine, the dicyclohexylcarbodiimide and the hydroxyethyl acrylate is (0.5-20 g): (0.05-2 g): (1.5-60 g): (0.3-12 mL); the dosage of the organic solvent meets the requirement that 10-300 mL of organic solvent is correspondingly added into every 0.5-20 g of lipoic acid;
the organic solvent is at least one of tetrahydrofuran, dichloromethane, chloroform and acetone;
the stirring reaction is carried out for 4-36 h in an ice bath, and a step of washing and purifying by deionized water is also included after the reaction is finished.
The stirring in the preparation method is to fully contact the raw materials and accelerate the reaction speed, and the conventional stirring speed in the field can be realized, so that the stirring speed is not limited, and the stirring speed is preferably 100-1000 rpm.
The bridging molecule for bonding the metal material and the hydrogel is applied to the realization of high-strength bonding of the hydrogel and the metal material interface, in particular to the application in the preparation of a bionic implantable medical device for combining a flexible hydrogel material and a rigid medical metal material.
The hydrogel includes various crosslinking mechanisms and R based on in situ polymerization1A hydrogel with groups that are crosslinked; the metal material includes various metals and alloys thereof commonly used in medical devices.
The application of the bridging molecule for bonding the metal material and the hydrogel in realizing the high-strength bonding of the hydrogel and the metal material interface specifically comprises the following steps:
(1) dissolving bridging molecules in a solvent to prepare a bridging molecule solution, and then acting on the surface of the metal material to obtain the surface of the metal material modified by the bridging molecules;
(2) and (2) coating the hydrogel precursor on the surface of the metal material modified by the bridging molecules obtained in the step (1), and reacting under certain conditions to simultaneously complete the curing of the hydrogel and the high-strength adhesion of the hydrogel to the metal material interface through the bridging molecules.
The solvent in the step (1) is at least one of acetone, ethanol, tetrahydrofuran, dichloromethane, trichloromethane and isopropanol.
The metal material in the step (1) is alloy or stainless steel formed by one or more than two of nickel, magnesium, titanium, chromium, aluminum, cobalt, gold, silver, platinum and other metals.
The mass fraction of bridging molecules in the bridging molecule solution in the step (1) is 0.1-10 wt%;
the dosage of the bridging molecule solution in the step (1) meets the following requirements: every 1cm2The surface of the metal material is correspondingly used with 0.001-10 mL of bridging molecule solution, preferably every 1cm2The surface of the metal material is correspondingly used with 0.001-0.01 mL of bridging molecular solution.
The step (1) of acting on the surface of the metal material is that the solution acts on the surface of the metal material through at least one of instant spraying, adhesion, dip coating and soaking, and the acting time is 0.01-24 hours;
the hydrogel precursor in the step (2) is selected from one of the following components A and B in parts by mass:
and (2) component A: 1.5-3.5 parts of polyethylene glycol diacrylate (PEGDA), 0.1-0.5 part of sodium alginate and 0.001-0.5 part of Ca2+The light-emitting material comprises a compound, 0.027-0.063 parts of a photoinitiator and 5-15 parts of water;
and (B) component: 1-4 parts of acrylamide (AAm), 0.1-0.5 part of sodium alginate and 0.001-0.5 part of Ca2+The composition comprises a compound, 0.02-0.04 parts of N, N' -dimethyl bisacrylamide (cross-linking agent), 0.025-0.095 parts of ammonium persulfate (initiator), 5-15 parts of water and 0.0025-0.01 part of tetramethylethylenediamine.
Ca-containing described in component A and component B2+The compound is calcium sulfate and carbonAt least one of calcium oxalate and calcium chloride.
The reaction of step (2) comprises a crosslinking curing reaction of the hydrogel precursor and an in situ polymerization reaction of the hydrogel and the bridging molecule, both reactions being carried out simultaneously. The crosslinking curing reaction is to irradiate for 0.01-24 hours under 200-400 nm ultraviolet light or 400-900 nm visible light; the in-situ polymerization reaction is carried out at room temperature for 0.01-24 h;
when the bridging molecule contains a stimuli-responsive group, the interface between the hydrogel and the metal material can be stress-separated if desired, as exemplified below.
When X is in the bridging molecule1-X2When the hydrogel contains pH sensitive groups, the stress separation method comprises the steps of coating acid and alkali reagents on the interface of the hydrogel and a metal material, changing the pH value of the environment, and dissociating the selected pH sensitive groups; when X is in the bridging molecule1-X2When the temperature sensitive groups are contained, the stress separation method is to change the temperature between 0 and 100 ℃ so as to destroy the molecular structure; when X is in the bridging molecule1-X2When the composition contains a redox sensitive group, the stress separation method comprises coating at least one of oxidized glutathione, reduced glutathione and dithiothreitol, or other reagents with similar reduction effect; the preferred amount of glutathione or dithiothreitol is 1cm2The adhesive interface (2) is used in an amount of 0.005 to 5 g.
The operation is carried out at room temperature when the temperature is not indicated, and the room temperature is 5-35 ℃.
The mechanism of the invention is as follows:
the invention starts from the chemical structure of functional groups forming a hydrogel polymer network and the self attribute of a metal material, functional groups which can respectively act with the metal surface and the hydrogel are introduced into bridging molecules, and chemical crosslinking sites of molecular terminal groups of the functional groups are designed (such as the copolymerization crosslinking of double bonds of the bridging molecular terminal groups and the hydrogel and the coordination of terminal carboxyl and the metal). Furthermore, a responsive group is introduced into the molecule, so that the on-demand cleavage of the bridging molecule can be realized under the stimulation of a proper external signal. By taking the bridging molecule as a molecular interface tie, chemical anchor points can be accessed to various metal surfaces by in-situ spraying, dip coating and other instant and efficient surface modification methods, and two end group functional groups of the bridging molecule can be respectively bonded with the hydrogel and the metal surfaces by in-situ polymerization reaction, so that the high-strength bonding effect between the two is achieved. When the bridging molecule containing the responsive group is used, the bridging molecule can be quickly disconnected through response of external stimulus on the basis of realizing high-strength adhesion, so that the hydrogel and the metal can achieve the effect of separating according to requirements.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the bridging molecule of the invention has simple synthesis and good repeatability, can be prepared in an amplification way, has convenient, efficient and mild whole surface treatment and bonding process, has better biological safety, is expected to be widely applied to the relevant fields of biomedicine, and has higher clinical application value.
Drawings
FIG. 1 is a drawing of bridged molecule 1 prepared in example 11H NMR spectrum.
FIG. 2 is a drawing of bridged molecule 2 prepared in example 31H NMR spectrum.
FIG. 3 is a drawing of bridged molecule 3 prepared in example 71H NMR spectrum.
Fig. 4 is a macroscopic view of the bonding interface (a) of the blank aluminum surface and the hydrogel and the bonding interface (b) of the bridging molecule 1 modified aluminum surface and the hydrogel prepared in example 9.
FIG. 5 is a schematic view showing the process of bonding a bridging molecule to a metal substrate and a hydrogel and separating an interface using glutathione in the present invention.
Fig. 6 is a macroscopic view of the bonding interface (a) of the blank aluminum surface and the hydrogel and the bonding interface (b) of the bridging molecule 2 modified aluminum surface and the hydrogel prepared in example 12.
FIG. 7 is a graph showing the separation of hydrogel from metal after glutathione was applied to the interface junction in example 12.
FIG. 8 is a graph showing the peel-off curves of the adhesion interface of the bridging molecule 2 modified stainless steel surface and hydrogel prepared in example 13 and the adhesion interface of the blank stainless steel surface and hydrogel.
FIG. 9 is a diagram showing the separation process of the hydrogel from the substrate surface before (a) and after (b) the glutathione treatment in example 13.
FIG. 10 is a graph showing the interfacial peel strength before and after glutathione was applied to the interfacial bond in example 14.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the present invention are not limited thereto.
The reagents used in the examples are commercially available without specific reference. In the examples, temperatures not indicated are all those carried out at room temperature.
Example 1
1g of 12-aminododecanoic acid and 1mL of triethylamine were dissolved in 20mL of tetrahydrofuran, followed by addition of 1mL of methacrylic anhydride and mechanical stirring (1000 rpm) in an ice-water bath for 4 h. Followed by extraction with 1L of deionized water to remove impurities and obtain the bridged molecule 1.
NMR spectrum of the bridged molecule prepared in this example: (1H NMR) is shown in fig. 1, and it can be seen from fig. 1 that the present invention successfully synthesized the bridged molecule 1.
Example 2
10g of 12-aminododecanoic acid and 50mL of triethylamine were dissolved in 300mL of tetrahydrofuran, followed by addition of 20mL of methacrylic anhydride and mechanical stirring (300 rpm) in an ice-water bath for 36 h. Followed by extraction with 10L of deionized water to remove impurities and obtain the bridged molecule 1.
NMR spectrum of the bridged molecule prepared in this example: (1H NMR) is consistent with figure 1, indicating that the present invention successfully synthesized bridged molecule 1.
Example 3
Dissolving 0.1g of dithiodiglycolic acid in 1.0mL of acetic anhydride, reacting for 24 hours at 0 ℃ to obtain cyclic dithioic anhydride, adding 0.2g of hydroxyethyl methacrylate and 10mL of dichloromethane, mechanically stirring (rotating speed of 100rpm) for 72 hours in an ice-water bath environment, and finally purifying by using a gel chromatographic column under the action of a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1 to obtain the bridging molecule 2.
NMR spectrum of bridged molecule 2 prepared in this example: (1H NMR) as shown in fig. 2, it can be seen from fig. 2 that the present invention successfully synthesized the bridged molecule 2.
Example 4
Dissolving 2.0g of dithiodiglycolic acid in 20mL of acetic anhydride, reacting for 4 hours at 40 ℃ to obtain cyclic dithioic anhydride, adding 2.0g of hydroxyethyl methacrylate and 30mL of dichloromethane, mechanically stirring (the rotating speed is 1000rpm) for 12 hours in an ice-water bath environment, and finally purifying by using a gel chromatographic column under the action of a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 0.5:1 to obtain the bridging molecule 2.
NMR spectrum of bridged molecule 2 prepared in this example: (1H NMR) is consistent with figure 2, indicating that the present invention successfully synthesized the bridged molecule 2.
Example 5
Dissolving 1.82g of dithiodiglycolic acid in 15mL of acetic anhydride, reacting for 18 hours at 25 ℃ to obtain cyclic dithioic anhydride, adding 1.6g of hydroxyethyl methacrylate and 25mL of dichloromethane, mechanically stirring (rotating speed is 600rpm) for 18 hours in an ice-water bath environment, and finally purifying by using a gel chromatographic column under the action of a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1 to obtain the bridging molecule 2.
NMR spectrum of bridged molecule 2 prepared in this example: (1H NMR) is consistent with figure 2, indicating that the present invention successfully synthesized the bridged molecule 2.
Example 6
Dissolving 1.5g of dithiodiglycolic acid in 12mL of acetic anhydride, reacting for 12 hours at 30 ℃ to obtain cyclic dithioic anhydride, adding 1.3g of hydroxyethyl methacrylate and 20mL of dichloromethane, mechanically stirring (the rotating speed is 300rpm) for 20 hours in an ice-water bath environment, and finally purifying by using a gel chromatographic column under the action of a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1.5:1 to obtain the bridging molecule 2.
NMR spectrum of bridged molecule 2 prepared in this example: (1H NMR) is consistent with figure 2, indicating that the present invention successfully synthesized the bridged molecule 2.
Example 7
0.5g of lipoic acid, 0.05g of 4-dimethylaminopyridine, 1.5g of dicyclohexylcarbodiimide and 0.3mL of hydroxyethyl acrylate were added to tetrahydrofuran (10mL) in an ice bath environment and the reaction was completed by mechanical stirring (700 rpm) for 4 h. Followed by washing with 1L of ionized water to obtain the bridging molecule 3.
NMR spectrum of bridged molecule 3 prepared in this example: (1H NMR) as shown in fig. 3, it can be seen from fig. 3 that the present invention successfully synthesized the bridged molecule 3.
Example 8
20g of lipoic acid, 2g of 4-dimethylaminopyridine, 60g of dicyclohexylcarbodiimide and 12mL of hydroxyethyl acrylate were added to dichloromethane (300mL) in an ice bath environment, and the reaction was completed by mechanical stirring (100 rpm) for 36 h. Followed by washing with 10L of ionized water to obtain the bridging molecule 3.
NMR spectrum of bridged molecule 3 prepared in this example: (1H NMR) is consistent with figure 3, indicating that the present invention successfully synthesized bridged molecule 3.
Example 9
(1) The bridging molecule 1 prepared in example 1 was dissolved in absolute ethanol to prepare a solution of the bridging molecule with a concentration of 1 wt%, and the solution was sprayed on the surface of aluminum metal (10 mL/cm)2) Reacting for 1h to obtain the bridging molecule 1 modified aluminum surface;
(2) dissolving 1.5g of PEGDA (Mn is 20000), 0.10g of natural polymer sodium alginate and 27mg of photoinitiator Irgacure 2959 in 5mL of deionized water, and then adding 68mg of calcium sulfate and uniformly mixing to obtain a hydrogel precursor;
(3) and (3) taking the aluminum surface modified by the bridging molecule 1 obtained in the step (1) as a substrate, coating the hydrogel precursor obtained in the step (2) on the aluminum surface modified by the bridging molecule 1, and reacting for 4h to finish hydrogel-aluminum interface adhesion, wherein the preparation of the hydrogel is finished after 1h of ultraviolet crosslinking and curing at 200nm, and the hydrogel-aluminum interface adhesion is finished through in-situ polymerization reaction for 4 h.
As a control, the hydrogel was crosslinked and cured on the surface of the bare aluminum in the same manner as in step (3), and the hydrogel-aluminum interfacial adhesion was completed.
Fig. 4 is a macroscopic view of the bonding interface (a) of the blank aluminum surface and the hydrogel and the bonding interface (b) of the bridging molecule 1 modified aluminum surface and the hydrogel prepared in example 9. As can be seen from FIG. 4, due to the presence of the bridging molecule 1, the hydrogel and metal interface are strongly adhered, and a typical tearing phenomenon is observed when peeling is performed.
Example 10
(1) The bridging molecule 1 prepared in example 2 was dissolved in ethanol to prepare a solution of the bridging molecule with a concentration of 1 wt%, and the solution was dip-coated on the surface of metallic nickel (1 mL/cm)2) Reacting for 0.5h to obtain a nickel surface modified by bridging molecules 1;
(2) uniformly mixing 4.0g of AAm monomer, 0.50g of natural polymer sodium alginate, 10mg of calcium sulfate, 40mg of N, N' -dimethyl bisacrylamide (cross-linking agent), 95mg of ammonium persulfate (initiator), 15mL of deionized water (solvent) and 10mg of tetramethylethylenediamine to obtain a hydrogel precursor;
(3) and (3) taking the nickel surface modified by the bridging molecule 1 prepared in the step (1) as a substrate, coating the hydrogel precursor obtained in the step (2) on the nickel surface modified by the bridging molecule 1, and reacting for 18h to finish hydrogel-nickel interface adhesion, wherein the hydrogel preparation is finished after the 400nm visible light is crosslinked and cured for 15h, and the hydrogel-nickel interface adhesion is finished through in-situ polymerization for 18 h.
Example 11
(1) The bridging molecule 2 prepared in example 3 was dissolved in absolute ethanol to prepare a 0.1 wt% solution of the bridging molecule, which was sprayed on the surface of metallic titanium (10 mL/cm)2) Reacting for 0.01h to obtain a titanium surface modified by bridging molecules 2;
(2) dissolving 1.5g of PEGDA (Mn is 20000), 0.10g of natural polymer sodium alginate and 27mg of photoinitiator Irgacure 2959 in 5mL of deionized water, and then adding 68mg of calcium sulfate and uniformly mixing to obtain a hydrogel precursor;
(3) and (2) taking the titanium surface modified by the bridging molecule 2 obtained in the step (1) as a substrate, coating the hydrogel precursor obtained in the step (2) on the titanium surface modified by the bridging molecule, and reacting for 4h to finish hydrogel-titanium interface adhesion, wherein the preparation of the hydrogel is finished after the ultraviolet light with the wavelength of 200nm is crosslinked and cured for 0.5h, and the hydrogel-titanium interface adhesion is finished through in-situ polymerization for 4 h.
Glutathione is applied to the interface bonding part at an amount of 0.005g/cm2And detecting the separation process of the hydrogel and the titanium surface modified by the bridging molecule, wherein the process of bonding the metal substrate and the hydrogel by the bridging molecule and utilizing a glutathione separation interface is schematically shown in fig. 5.
Example 12
(1) The bridging molecule 2 prepared in example 4 was dissolved in tetrahydrofuran to prepare a solution of 10 wt% bridging molecule, which was sprayed on the surface of aluminum metal (0.001 mL/cm)2) Reacting for 24 hours to obtain the bridging molecule 2 modified aluminum surface;
(2) dissolving 3.5g of PEGDA (Mn is 20000), 0.10g of natural polymer sodium alginate and 63mg of photoinitiator Irgacure 2959 in 15mL of deionized water, and then adding 340mg of calcium sulfate and uniformly mixing to obtain a hydrogel precursor;
(3) and (2) taking the aluminum surface modified by the bridging molecule 2 obtained in the step (1) as a substrate, coating the hydrogel precursor obtained in the step (2) on the aluminum surface modified by the bridging molecule, and reacting for 24 hours to finish hydrogel-aluminum interface adhesion, wherein the preparation of the hydrogel is finished after the crosslinking and curing of 400nm ultraviolet light for 24 hours, and the hydrogel-aluminum interface adhesion is finished through in-situ polymerization for 24 hours.
As a control, the hydrogel was crosslinked and cured on the surface of the bare aluminum in the same manner as in step (3), and the hydrogel-aluminum interfacial adhesion was completed.
And (3) detecting the adhesion condition of the substrate at the interface between the bridging molecule 2 and the substrate before and after modification, wherein fig. 6 is a macroscopic view of the adhesion interface (a) between the blank aluminum surface and the hydrogel and the adhesion interface (b) between the bridging molecule 2 modified aluminum surface and the hydrogel prepared in example 12. As can be seen from FIG. 6, due to the presence of the bridging molecule 2, the hydrogel and metal interface are strongly adhered, and a typical tearing phenomenon can be seen when peeling is performed.
Glutathione is acted on the interface bonding part, and the dosage is 5g/cm2FIG. 7 is a graph showing the separation of the hydrogel from the metal after glutathione is applied to the interface bonding site in example 12. It can be seen from the figure that the hydrogel is separated from the metal and glutathione breaks the disulfide bonds in the bridging molecule 2, thereby breaking the bridging molecule 2.
Example 13
(1) The bridged molecule 2 prepared in example 5 was dissolved in absolute ethanol to prepare a solution of the bridged molecule 2 with a concentration of 1 wt%, and the solution was infiltrated on the surface of stainless steel metal (0.01 mL/cm)2) Reacting for 0.1h to obtain the stainless steel surface modified by the bridging molecule 2;
(2) mixing 1.0g of AAm monomer, 0.15g of natural polymer sodium alginate, 5mg of calcium sulfate, 20mg of N, N' -dimethyl bisacrylamide (cross-linking agent), 25mg of ammonium persulfate (initiator), 5mL of deionized water (solvent) and 2.5mg of tetramethyl ethylenediamine to prepare a hydrogel precursor;
(3) and (2) taking the bridging molecule 2 modified stainless steel surface prepared in the step (1) as a substrate, coating the hydrogel precursor obtained in the step (2) on the bridging molecule 2 modified stainless steel surface, and reacting for 18h to finish hydrogel-stainless steel interfacial adhesion, wherein the hydrogel preparation is finished after 1h of crosslinking and curing by 900nm visible light, and the hydrogel-stainless steel interfacial adhesion is finished through 18h of in-situ polymerization reaction.
As a control, the hydrogel was cross-linked and cured on the surface of the blank stainless steel in the same manner as in step (3), thereby completing the hydrogel-stainless steel interfacial adhesion.
The interface adhesive strength of the hydrogel-stainless steel before and after modification of the bridging molecule 2 was quantitatively tested by a peel strength tester. FIG. 8 is a graph showing the peel-off curves of the adhesion interface of the bridging molecule 2 modified stainless steel surface and hydrogel prepared in example 13 and the adhesion interface of the blank stainless steel surface and hydrogel. The results show that the bonding strength of the stainless steel-hydrogel interface modified by the bridging molecule 2 is much higher than that of the blank stainless steel-hydrogel, which indicates that the bridging molecule 2 prepared by the invention can realize high-strength bonding between the hydrogel and the rigid medical metal material.
Glutathione can be used asThe dosage of the interface bonding part of the stainless steel surface modified by bridging molecules 2 and the hydrogel is 0.5g/cm2The separation process of the hydrogel from the bridging molecule 2 modified stainless steel surface was investigated. FIG. 9 shows the separation process of the hydrogel from the substrate surface before (a) and after (b) glutathione treatment.
Example 14
(1) The bridged molecule 2 prepared in example 6 was dissolved in methylene chloride to prepare a solution of the bridged molecule 2 at a concentration of 1 wt%, and the solution was dip-coated on the surface of metallic nickel (0.01 mL/cm)2) Reacting for 0.5h to obtain a nickel surface modified by bridging molecules 2;
(2) uniformly mixing 4.0g of AAm monomer, 0.50g of natural polymer sodium alginate, 10mg of calcium sulfate, 40mg of N, N' -dimethyl bisacrylamide (cross-linking agent), 95mg of ammonium persulfate (initiator), 15mL of deionized water (solvent) and 10mg of tetramethylethylenediamine to obtain a hydrogel precursor;
(3) and (2) taking the nickel surface modified by the bridging molecule 2 prepared in the step (1) as a substrate, coating the hydrogel precursor obtained in the step (2) on the nickel surface modified by the bridging molecule, and reacting for 18h to finish hydrogel-nickel interface adhesion, wherein the hydrogel preparation is finished after the 400nm visible light is crosslinked and cured for 15h, and the hydrogel-nickel interface adhesion is finished through in-situ polymerization for 18 h.
Glutathione is applied to the interface bonding part at an amount of 0.25g/cm2The quantitative test is carried out by adopting a peel strength tester, and the change of the peel strength before and after the glutathione is added. FIG. 10 is a graph showing the interfacial peel strength before and after glutathione was applied to the interfacial bond in example 14. It can be seen that the adhesion was lost due to disruption of the bridging molecule 2 structure by glutathione, and its adhesive strength was significantly reduced.
Example 15
(1) The bridged molecule 2 prepared in example 5 was dissolved in isopropanol to prepare a solution of the bridged molecule 2 at a concentration of 1 wt%, and metallic cobalt was immersed in the solution (0.01 mL/cm)2) Reacting for 0.1h to obtain a bridging molecule 2 modified cobalt surface;
(2) dissolving 2.5g of PEGDA (Mn is 20000), 0.15g of natural polymer sodium alginate and 30mg of photoinitiator Irgacure 2959 in 10mL of deionized water, and then adding 80mg of calcium sulfate and uniformly mixing to obtain a hydrogel precursor;
(3) and (2) taking the cobalt surface modified by the bridging molecule 2 prepared in the step (1) as a substrate, coating the hydrogel precursor obtained in the step (2) on the cobalt surface modified by the bridging molecule 2, and reacting for 24h to finish hydrogel-cobalt interface adhesion, wherein the preparation of hydrogel is finished after the crosslinking and curing of 200nm ultraviolet light for 4h, and the hydrogel-cobalt interface adhesion is finished through in-situ polymerization for 24 h.
Dithiothreitol is acted on the interface bonding part, and the dosage is 0.1g/cm2Separation of the hydrogel from the metal material substrate was also observed.
Example 16
(1) The bridged molecule 2 prepared in example 4 was dissolved in acetone to prepare a solution of the bridged molecule 2 having a concentration of 0.5 wt%, and the solution was sprayed on the surface of chromium metal (0.01 mL/cm)2) Reacting for 0.1h to obtain a chromium surface modified by bridging molecules 2;
(2) uniformly mixing 2.5g of AAm monomer, 0.20g of natural polymer sodium alginate, 6mg of calcium sulfate, 25mg of N, N' -dimethyl bisacrylamide (cross-linking agent), 80mg of ammonium persulfate (initiator), 12.5mL of deionized water (solvent) and 7.5mg of tetramethyl ethylenediamine to obtain a hydrogel precursor;
(3) and (2) taking the chromium surface modified by the bridging molecule 2 prepared in the step (1) as a substrate, coating the hydrogel precursor obtained in the step (2) on the chromium surface modified by the bridging molecule 2, and reacting for 18h to finish hydrogel-chromium interface adhesion, wherein the preparation of the hydrogel is finished after 24h of visible light crosslinking and curing at 450nm, and the hydrogel-chromium interface adhesion is finished through in-situ polymerization reaction for 24 h.
Dithiothreitol is acted on the interface bonding part, and the dosage is 2g/cm2Separation of the hydrogel from the metal substrate material was also observed.
Example 17
(1) The bridging molecule 3 prepared in example 7 was dissolved in tetrahydrofuran to prepare a 0.1 wt% solution of the bridging molecule, which was then dip-coated onto a copper metal surface (1 mL/cm)2) Reacting for 0.8h to obtain a copper surface modified by bridging molecules 3;
(2) uniformly mixing 4.0g of AAm monomer, 0.50g of natural polymer sodium alginate, 10mg of calcium sulfate, 40mg of N, N' -dimethyl bisacrylamide (cross-linking agent), 95mg of ammonium persulfate (initiator), 15mL of deionized water (solvent) and 10mg of tetramethylethylenediamine to obtain a hydrogel precursor;
(3) and (2) taking the copper surface modified by the bridging molecule 3 prepared in the step (1) as a substrate, coating the hydrogel precursor obtained in the step (2) on the copper surface modified by the bridging molecule 3, and reacting for 20h to finish hydrogel-copper interface adhesion, wherein the preparation of the hydrogel is finished after the 400nm visible light is crosslinked and cured for 15h, and the hydrogel-copper interface adhesion is finished through in-situ polymerization reaction for 20 h. Typical tearing phenomena are seen when peeling is performed.
Example 18
(1) The bridging molecule 3 prepared in example 8 was dissolved in ethanol to prepare a solution of the bridging molecule with a concentration of 1 wt%, and the solution was dip-coated on the surface of gold metal (5 mL/cm)2) Reacting for 1h to obtain a bridging molecule 3 modified gold surface;
(2) uniformly mixing 4.0g of AAm monomer, 0.50g of natural polymer sodium alginate, 10mg of calcium sulfate, 40mg of N, N' -dimethyl bisacrylamide (cross-linking agent), 95mg of ammonium persulfate (initiator), 15mL of deionized water (solvent) and 10mg of tetramethylethylenediamine to obtain a hydrogel precursor;
(3) and (2) taking the gold surface modified by the bridging molecules 3 prepared in the step (1) as a substrate, coating the hydrogel precursor obtained in the step (2) on the gold surface modified by the bridging molecules 3, and reacting for 18h to finish hydrogel-gold interface adhesion, wherein 200nm ultraviolet light is used for crosslinking and curing for 18h to finish hydrogel preparation, and simultaneously, performing in-situ polymerization for 24h to finish hydrogel-nickel interface adhesion. Typical tearing phenomena are seen when peeling is performed.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (7)
1. Use of a bridging molecule for bonding a metal material to a hydrogel in the interfacial adhesion of the hydrogel to the metal material, wherein the bridging molecule has the formula of one of the following:
bridging molecule 1
A bridging molecule 2.
2. Use of a bridging molecule for bonding a metal material to a hydrogel according to claim 1 in interfacial adhesion of hydrogel to metal material, wherein:
when the bridging molecule is bridging molecule 1, the preparation method comprises the following steps: dissolving 12-aminododecanoic acid and triethylamine in an organic solvent, adding methacrylic anhydride, stirring for reaction, and obtaining a bridging molecule 1 after the reaction is finished;
when the bridging molecule is bridging molecule 2, the preparation method comprises the following steps: dissolving dithiodiglycol diacetic acid in acetic anhydride for reaction to obtain cyclic dithioic anhydride, dissolving the obtained cyclic dithioic anhydride and hydroxyethyl methacrylate in an organic solvent, and stirring for reaction to obtain bridging molecules 2.
3. Use of a bridging molecule for bonding a metal material to a hydrogel according to claim 2 in interfacial adhesion of hydrogel to metal material, wherein:
when the bridging molecule is bridging molecule 1:
the dosage ratio of the 12-aminododecanoic acid to the methacrylic anhydride to the triethylamine is 1-10.0 g: 1-20 mL: 1-50 mL; the dosage of the organic solvent is such that 20-300 mL of the organic solvent is correspondingly added into every 1-10 g of 12-aminododecanoic acid;
the organic solvent is at least one of tetrahydrofuran, dichloromethane, chloroform and acetone;
the stirring reaction is carried out in an ice water bath for 4-36 hours; after the stirring reaction is finished, the method also comprises the step of removing impurities by using deionized water for extraction;
when the bridging molecule is bridging molecule 2:
the dosage ratio of the dithiodiglycol diacetic acid to the acetic anhydride is 0.1-2.0 g: 1.0-20 mL; the dosage of the organic solvent is such that 10-30 mL of organic solvent is correspondingly added to every 0.2-2.0 g of hydroxyethyl methacrylate; the temperature for dissolving the dithiodiglycol diacetic acid in the acetic anhydride for reaction is 0-40 ℃, and the reaction time is 4-24 h;
the organic solvent is at least one of chloroform, N-dimethylformamide, acetone, tetrahydrofuran, isopropanol, N-dimethylacetamide and dichloromethane;
the dosage of the cyclic dithioic anhydride and the hydroxyethyl methacrylate meets the requirement that the mass ratio of the raw materials of the cyclic dithioic anhydride, namely the dithioic diglycol diacetate and the hydroxyethyl methacrylate is 0.1-2.0: 0.2 to 2.0; the dosage of the organic solvent is such that 10-30 mL of organic solvent is correspondingly added to every 0.2-2.0 g of hydroxyethyl methacrylate;
the stirring reaction is carried out for 12-72 h in an ice-water bath environment at the rotating speed of 100-1000 rpm, and the method further comprises a step of purifying by adopting a gel chromatographic column under the action of a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of (0.5-4): 1.
4. Use of a bridging molecule for bonding a metal material to a hydrogel according to claim 1 in interfacial adhesion of hydrogel to metal material, comprising in particular the steps of:
(1) dissolving bridging molecules in a solvent to prepare a bridging molecule solution, and then acting on the surface of the metal material to obtain the surface of the metal material modified by the bridging molecules;
(2) coating a hydrogel precursor on the surface of the metal material modified by the bridging molecules obtained in the step (1), and simultaneously completing the curing of the hydrogel and the adhesion of the hydrogel to the metal material interface through the bridging molecules through reaction under certain conditions.
5. Use of a bridging molecule for bonding a metal material to a hydrogel according to claim 4 in interfacial adhesion of hydrogel to metal material, wherein:
the solvent in the step (1) is at least one of acetone, ethanol, tetrahydrofuran, dichloromethane, trichloromethane and isopropanol;
the metal material in the step (1) is alloy or stainless steel formed by at least two of one or more of nickel, magnesium, titanium, aluminum, cobalt, gold, silver and platinum;
the mass fraction of bridging molecules in the bridging molecule solution in the step (1) is 0.1-10 wt%;
the dosage of the bridging molecule solution in the step (1) meets the following requirements: every 1cm2The surface of the metal material is correspondingly used with 0.001-10 mL of bridging molecular solution;
the step (1) of acting on the surface of the metal material is to act the solution on the surface of the metal material through at least one of instant spraying, adhesion, dip coating and soaking, and the acting time is 0.01-24 hours.
6. Use of a bridging molecule for bonding a metal material to a hydrogel according to claim 4 in interfacial adhesion of hydrogel to metal material, wherein:
the hydrogel precursor in the step (2) is selected from one of the following components A and B in parts by mass:
and (2) component A: 1.5 to 3.5 parts of polyethylene glycol diacrylate, 0.1 to 0.5 part of sodium alginate and 0.001 to 0.5 part of Ca2+The light-emitting material comprises a compound, 0.027-0.063 parts of a photoinitiator and 5-15 parts of water;
and (B) component: 1-4 parts of acrylamide, 0.1-0.5 part of sodium alginate and 0.001-0.5 part of Ca2+Compound (I), 0.02 to0.04 part of N, N' -dimethyl bisacrylamide, 0.025-0.095 part of ammonium persulfate, 5-15 parts of water and 0.0025-0.01 part of tetramethyl ethylene diamine;
ca-containing described in component A and component B2+The compound is at least one of calcium sulfate, calcium carbonate, calcium oxalate and calcium chloride;
the reaction in the step (2) comprises a crosslinking curing reaction of the hydrogel precursor and an in-situ polymerization reaction of the hydrogel and the bridging molecules, and the two reactions are carried out simultaneously; the crosslinking curing reaction is to irradiate for 0.01-24 hours under 200-400 nm ultraviolet light or 400-900 nm visible light; the in-situ polymerization reaction is carried out at room temperature for 0.01-24 h.
7. Use of a bridging molecule for bonding a metal material to a hydrogel according to claim 1 in interfacial adhesion of hydrogel to metal material, wherein:
when the bridging molecule contains a disulfide group, the interface between the hydrogel and the metal material is stress-separated by coating with at least one of oxidized glutathione, reduced glutathione and dithiothreitol.
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