CN113683787B - Hydrogel material with secondary crosslinking characteristic and preparation method and application thereof - Google Patents
Hydrogel material with secondary crosslinking characteristic and preparation method and application thereof Download PDFInfo
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- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
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- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/008—Hydrogels or hydrocolloids
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/043—Proteins; Polypeptides; Degradation products thereof
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/145—Hydrogels or hydrocolloids
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- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides a hydrogel material with secondary crosslinking characteristic, a preparation method and application thereof, wherein the hydrogel material is prepared by grafting catechol groups and photosensitive groups on any biological macromolecule of gelatin, alginate and hyaluronic acid to obtain catechol photosensitive macromolecules, and carrying out photocrosslinking after solution preparation and related application. After the hydrogel material is prepared into a solution, the photo-curing crosslinking of the photosensitive groups in the hydrogel molecules can be firstly utilized to prepare a specific shape, and the catechol groups in the hydrogel molecules can be utilized to crosslink again to realize adhesion between the hydrogel and tissues or splicing between hydrogels with different shapes. The hydrogel capable of being crosslinked for the second time has great application value in the preparation of wound dressing, conductive biosensor, tissue engineering scaffold and other fields.
Description
Technical Field
The invention relates to the technical field of preparation of high molecular hydrogel, in particular to a hydrogel material with secondary crosslinking characteristic, and a preparation method and application thereof.
Background
Skin incisions caused by trauma or surgery are prone to hyperplasia or sunken scars after surgical suturing, which affect the beauty. The use of tissue glue instead of surgical sutures can reduce scarring of the skin. There are currently a number of suture-free tissue glue products that are used to aid in adhesive care during surgical and cosmetic wound suturing. Such as Lanolin tissue glue (Histoacryl Tissue Adhesive), 3M tissue glue (Vetbond), which consist essentially of n-butyl 2-cyanoacrylate (Enb), and stabilizers (hydroquinone, sulfur dioxide, phosphoric acid). Such tissue glues have certain drawbacks: (1) the incision surface is required to be coated by a doctor manually, and the uniform coating is difficult to realize by the doctor manually; (2) it takes several minutes to wait for the glue to change from solution to solid; (3) the matrix material of the glue is not good enough in biocompatibility. Therefore, how to prepare a hydrogel material which can be crosslinked and formed in advance and can be adhered to the skin again closely is an urgent problem to be solved clinically.
In tissue engineering research, the tissue engineering micro-tissue can realize uniform loading of seed cells, so that the construction of the micro-tissue is a popular field, but in the current research, a plurality of micro-tissues are directly placed at a tissue defect part, and no orderly assembly of the micro-tissues is realized. Therefore, if the hydrogel can be firstly used for preparing the microstructure, and the secondary crosslinking characteristic of the hydrogel is utilized to orderly arrange different types of microstructure, the problem of assembling the microstructure is hopefully solved, and a new idea is provided for tissue engineering research.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a hydrogel material with secondary crosslinking characteristic, a preparation method and application thereof, and the prepared hydrogel material can be subjected to secondary crosslinking to realize adhesion between hydrogel and tissues or splicing between hydrogels with different shapes.
The technical scheme provided by the invention is as follows: a hydrogel material with secondary crosslinking characteristic is prepared by grafting catechol group and photosensitive group on any biological macromolecule of gelatin, alginate and hyaluronic acid to obtain catechol photosensitive macromolecule, dissolving and then carrying out photocrosslinking.
A preparation method of a hydrogel material with secondary crosslinking characteristics comprises the following steps:
(1) Dissolving gelatin in PBS solution, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, adjusting the pH of the solution to 4.5-5.5, and activating;
(2) Dissolving dopamine hydrochloride in PBS (phosphate buffer solution), dropwise adding the dopamine hydrochloride solution into the gelatin solution obtained in the step (1), placing the mixed solution in a constant-temperature shaking table, shaking in a dark place, dialyzing, and freeze-drying to obtain catechol gelatin;
(3) Dissolving the catechol gelatin prepared in the step (2) in MES buffer solution, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide into the solution after full dissolution, and performing activation after the pH of the solution is adjusted to 4.5-5.5;
(4) Dissolving 2-aminoethyl methacrylate hydrochloride in MES solution, dropwise adding the 2-aminoethyl methacrylate hydrochloride solution into the catechol-based gelatin solution obtained in the step (3), placing the mixed solution in a constant temperature shaking table, dialyzing after shaking in a dark place, and freeze-drying to obtain catechol-based photosensitive gelatin;
(5) Preparing catechol-based photosensitive gelatin obtained in the step (4) into an aqueous solution with the mass fraction of 5-20%, adding a photoinitiator, then dripping the solution into hydrogel molds with different shapes, and using ultraviolet light irradiation to cure the solution to obtain a sheet-shaped hydrogel dressing; or using a stereoscopic light projection 3D printer to prepare hydrogel dressings or stents of different shapes.
Further, the mass fraction of the gelatin dissolved in the PBS solution in the step (1) is 0.5% -2%, the mass fraction of the catechol-based gelatin dissolved in the MES buffer solution obtained in the step (2) is 0.5% -2%, and the mass ratio of the dopamine hydrochloride to the gelatin in the step (2) is 0.2-1:1.
further, the raw material gelatin adopted in the step (1) can be replaced by alginate or hyaluronic acid, the mass fraction of the alginate or the hyaluronic acid dissolved in PBS solution is 0.05% -0.5% and 0.01% -0.3%, respectively, and the mass fraction of the catechol-based alginate or the catechol-based hyaluronic acid dissolved in MES buffer solution obtained in the step (2) is 0.05% -0.5% and 0.01% -0.3%, respectively.
Further, the mass ratio of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to the N-hydroxysuccinimide added in the step (1) and the step (3) is 5:3-1:1, wherein the mass concentration of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in the solution is 0.1-1%, and the activation time of the step (1) and the step (3) is 5-60min.
Further, in the step (2), the dopamine hydrochloride is prepared into 5-10% of mass concentration in PBS solution, the temperature of light-shielding oscillation is 20-40 ℃, the oscillation time is 5-24 hours, the pore size of the dialysis bag is 3000Da-1000000Da, and the dialysis time is 24-48 hours.
Further, in the step (4), the 2-aminoethyl methacrylate hydrochloride is dissolved in an MES solution to prepare a mass concentration of 5-10%, and the mass ratio of the 2-aminoethyl methacrylate hydrochloride to catechol-based gelatin is 0.2-1:1, the temperature of light-shielding oscillation is 20-40 ℃, the oscillation time is 5-24 hours, the pore space of the dialysis bag is 3000Da-1000000Da, and the dialysis time is 24-48 hours.
Furthermore, 365nm ultraviolet light is adopted in the step (5), the illumination time is between 5 and 30 seconds, the photoinitiator is LAP or I2959, and the added mass concentration is between 0.1 and 1 percent.
The hydrogel material with the secondary crosslinking characteristic obtained by the preparation method is prepared into 0.1-1mM/L ferric chloride solution or 0.1-1mM/L sodium periodate solution, a layer of solution is coated on the skin, and then the hydrogel material is stuck on the surface of the skin, so that tight adhesion can be realized; or the two hydrogels are stuck together, and ferric chloride solution or sodium periodate solution is added dropwise to the surfaces of the hydrogels, so that the tight adhesion can be realized.
The application of the hydrogel material with the secondary crosslinking characteristic utilizes a photocuring 3D printing technology to prepare a millimeter-sized hydrogel microcell by using the hydrogel material; by utilizing the secondary crosslinking characteristic of the hydrogel, the splicing among a plurality of hydrogel microcells and the tight adhesion between the hydrogel and tissues are achieved, and the accurate repair of the defect part is realized; or the hydrogel material is prepared into a skin wound dressing with a specific shape in advance by using a photocuring 3D printing technology, and the hydrogel material is tightly adhered to the skin by using the secondary crosslinking characteristic of the hydrogel, so that the effect of covering the wound surface and promoting skin repair is achieved.
The hydrogel material prepared by the method has the characteristic of secondary crosslinking, after the material is prepared into a solution, the photo-curing crosslinking of the photosensitive groups in the hydrogel molecules can be firstly utilized to prepare a specific shape, and the catechol groups in the hydrogel molecules can be utilized to crosslink again, so that the adhesion between the hydrogel and tissues or the splicing between hydrogels with different shapes can be realized. The hydrogel capable of being crosslinked for the second time has great application value in the preparation of wound dressing, conductive biosensor, tissue engineering scaffold and other fields.
Drawings
FIG. 1 is a flow chart of a method of preparation of the present invention;
FIG. 2 is a physical diagram of the chemical synthesis steps and corresponding products of the present invention;
FIG. 3 is a graph showing the results of nuclear magnetic resonance hydrogen spectroscopy of the hydrogel material of the present invention;
FIG. 4 is a graph of the results of Fourier infrared spectroscopy of a hydrogel material in accordance with the present invention;
FIG. 5 is a diagram of a tissue engineering chamber model of a hydrogel material of the present invention printed by a 3D printer;
FIG. 6 is a graph showing the effect of the hydrogel material of the present invention after secondary crosslinking;
FIG. 7 is a graph showing the effect of the hydrogel material of the present invention on tissue adhesion;
FIG. 8 is an electron micrograph of a hydrogel material prepared using dialysis bags of different molecular weights in accordance with the present invention;
FIG. 9 is a graph of in vitro degradation rates of hydrogel materials prepared using dialysis bags of varying molecular weights in accordance with the present invention;
FIG. 10 is a graph showing the results of swelling detection in physiological saline of a hydrogel material;
FIG. 11 is a graph of hardness test results of hydrogel materials;
FIG. 12 is a graph of the elastic test results of hydrogel materials;
FIG. 13 is a cytophotomicrograph of photocrosslinking of a hydrogel material mixed with bone marrow mesenchymal stem cells (BMSCs);
FIG. 14 is a cytophotomicrograph of photocrosslinking of a hydrogel material after mixing with Human Umbilical Vein Endothelial Cells (HUVECs);
FIG. 15 is a graph showing cell survival observed after 1 day and 5 days of incubation of the hydrogel material with HUVEC after photo-crosslinking;
FIG. 16 is a flow chart of the application of the hydrogel material of the present invention;
Detailed Description
The invention will be further illustrated with reference to specific examples.
Example 1
Dissolving gelatin in PBS solution to obtain 2% solution, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) into the solution after full dissolution, wherein the mass of EDC/NHS is 5/3 and the mass concentration of EDC in the solution is 0.5%, adjusting the pH of the solution to 5, and activating for 30 minutes. Preparing a solution with the mass fraction of 10% of dopamine hydrochloride in PBS solution, dropwise adding the dopamine hydrochloride solution into gelatin solution, wherein the mass ratio of gelatin to dopamine hydrochloride in the mixed solution is 2:1. the mixture was placed in a thermostatted shaker and shaken overnight at 25℃in the absence of light. The solution was dialyzed for 36 hours using a dialysis bag (pore at 3500 Da) and changed 6 times. And freeze-drying to obtain catechol-based gelatin.
Dissolving the prepared catechol-based gelatin in MES buffer solution to prepare a solution with the mass fraction of 1%, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) into the solution after the catechol-based gelatin is fully dissolved, wherein the mass of EDC/NHS is 5/3, the mass concentration of EDC in the solution is 1%, adjusting the pH of the solution to 5, and activating for 30 minutes. Preparing a solution with the mass fraction of 5% by taking 2-aminoethyl methacrylate hydrochloride (AEMA) in an MES solution, and dropwise adding the 2-aminoethyl methacrylate hydrochloride into a catechol-based gelatin solution, wherein the mass ratio of the 2-aminoethyl methacrylate hydrochloride to the catechol-based gelatin is 0.5:1. the mixture was placed in a thermostatted shaker and shaken overnight at 25℃in the absence of light. The solution was dialyzed using dialysis bags (pore at 3500 Da) for 36 hours, changing every 6 hours. Freeze drying to obtain catechol-based photosensitive gelatin with mixed molecular weight.
Dripping catechol-based photosensitive gelatin solution with the mass concentration of 15% into hydrogel molds with different shapes, adding photo-initiator phenyl-2, 4, 6-trimethyl benzoyl lithium phosphite (LAP) with the mass concentration of 0.5%, irradiating with 365nm ultraviolet light for 20 seconds, and solidifying the solution to obtain a sheet-shaped hydrogel dressing; or using a stereoscopic light projection 3D printer to prepare hydrogel dressings or stents of different shapes.
Example 2
Dissolving gelatin in PBS solution to obtain 2% solution, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) into the solution after full dissolution, wherein the mass of EDC/NHS is 5/3 and the mass concentration of EDC in the solution is 0.5%, adjusting the pH of the solution to 5, and activating for 30 minutes. And preparing the dopamine hydrochloride into a solution with the mass fraction of 10% in PBS solution. Adding the dopamine hydrochloride solution into the gelatin solution drop by drop, wherein the mass ratio of gelatin to dopamine hydrochloride in the mixed solution is 2:1. the mixture was placed in a thermostatted shaker and shaken overnight at 25℃in the absence of light. The solution was dialyzed for 36 hours using a dialysis bag (pore at 1000000 Da) and changed 6 times. And freeze-drying to obtain catechol-based gelatin.
Dissolving the prepared catechol-based gelatin in MES buffer solution to prepare a solution with the mass fraction of 1%, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) into the solution after the catechol-based gelatin is fully dissolved, wherein the mass of EDC/NHS is 5/3, the mass concentration of EDC in the solution is 1%, adjusting the pH of the solution to 5, and activating for 30 minutes. Preparing a solution with the mass fraction of 5% by taking 2-aminoethyl methacrylate hydrochloride (AEMA) in an MES solution, and dropwise adding the 2-aminoethyl methacrylate hydrochloride into a catechol-based gelatin solution, wherein the mass ratio of the 2-aminoethyl methacrylate hydrochloride to the catechol-based gelatin is 0.5:1. the mixture was placed in a thermostatted shaker and shaken overnight at 25℃in the absence of light. The solution was dialyzed using a dialysis bag (pore at 1000000 Da) for 36 hours, changing every 6 hours. And freeze-drying to obtain the catechol-based photosensitive gelatin with high molecular weight.
Dripping catechol-based photosensitive gelatin solution with the mass concentration of 15% into hydrogel molds with different shapes, adding photo-initiator phenyl-2, 4, 6-trimethyl benzoyl lithium phosphite (LAP) with the concentration of 0.5%, irradiating with 365nm ultraviolet light for 20 seconds, and solidifying the solution to obtain a sheet-shaped hydrogel dressing; or using a stereoscopic light projection 3D printer to prepare hydrogel dressings or stents of different shapes.
Catechol-based photosensitive gelatins of different molecular weights were prepared in examples 1 and 2, namely 3500Da and 1000kDa GDMA in the experimental detection results
Example 3
Dissolving gelatin in PBS solution to obtain 2% solution, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) into the solution after full dissolution, wherein the mass of EDC/NHS is 5/3 and the mass concentration of EDC in the solution is 0.5%, adjusting the pH of the solution to 5, and activating for 30 minutes. Preparing a solution with the mass fraction of 10% of dopamine hydrochloride in PBS solution, dropwise adding the dopamine hydrochloride solution into gelatin solution, wherein the mass ratio of gelatin to dopamine hydrochloride in the mixed solution is 3:1. the mixture was placed in a thermostatted shaker and shaken overnight at 25℃in the absence of light. The solution was dialyzed for 36 hours using a dialysis bag (pore at 3500 Da) and changed 6 times. And freeze-drying to obtain catechol-based gelatin.
Dissolving the prepared catechol-based gelatin in MES buffer solution to prepare a solution with the mass fraction of 1%, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) into the solution after the catechol-based gelatin is fully dissolved, wherein the mass of EDC/NHS is 5/3, the mass concentration of EDC in the solution is 1%, adjusting the pH of the solution to 5, and activating for 30 minutes. Preparing a solution with the mass fraction of 5% by taking 2-aminoethyl methacrylate hydrochloride (AEMA) in an MES solution, and dropwise adding the 2-aminoethyl methacrylate hydrochloride into a catechol-based gelatin solution, wherein the mass ratio of the 2-aminoethyl methacrylate hydrochloride to the catechol-based gelatin is 0.3:1. the mixture was placed in a thermostatted shaker and shaken overnight at 25℃in the absence of light. The solution was dialyzed using dialysis bags (pore at 3500 Da) for 36 hours, changing every 6 hours. And freeze-drying to obtain the catechol-based photosensitive gelatin with high molecular weight. Dripping catechol-based photosensitive gelatin solution with the mass concentration of 15% into hydrogel molds with different shapes, adding photo-initiator phenyl-2, 4, 6-trimethyl benzoyl lithium phosphite (LAP) with the concentration of 0.5%, irradiating with 365nm ultraviolet light for 20 seconds, and solidifying the solution to obtain a sheet-shaped hydrogel dressing; or using a stereoscopic light projection 3D printer to prepare hydrogel dressings or stents of different shapes.
Example 3 reduced the concentration of dopamine hydrochloride and 2-aminoethylmethacrylate hydrochloride compared to example 1 and reduced the grafting of the reaction product.
Example 4
Dissolving sodium alginate in PBS solution to obtain 0.2% solution, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) into the solution after full dissolution, wherein the mass of EDC/NHS is 3/2 and the concentration of EDC in the solution is 0.2%, adjusting the pH of the solution to 5, and activating for 10 minutes. The dopamine hydrochloride is prepared into 8% concentration in PBS solution, and the dopamine hydrochloride solution is added into the alginate solution drop by drop. The mixture was placed in a thermostatted shaker and shaken overnight at 35℃in the absence of light. The solution was dialyzed using a dialysis bag (pore at 3000 Da) for 48 hours, changing every 6 hours. Freeze drying to obtain catechol sodium alginate.
Dissolving the prepared catechol sodium alginate in MES buffer solution to prepare a solution with the mass fraction of 0.2%, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) into the solution after the solution is fully dissolved, wherein the mass of EDC/NHS is 3/2, the concentration of EDC in the solution is 1%, adjusting the pH of the solution to 5, and activating for 50 minutes. 2-aminoethyl methacrylate hydrochloride (AEMA) is prepared into a solution with the mass fraction of 5% in an MES solution, and the 2-aminoethyl methacrylate hydrochloride solution is added into a catechol-based alginate solution in one drop. The mixture was placed in a thermostatted shaker and shaken overnight at 35℃in the absence of light. The solution was dialyzed using a dialysis bag (pore at 3000 Da) for 48 hours, changing every 6 hours. Freeze drying to obtain catechol-based photosensitive alginate.
Dripping 3% concentration catechol sodium alginate solution into hydrogel molds of different shapes, adding 0.5% concentration of photoinitiator phenyl-2, 4, 6-trimethyl benzoyl lithium phosphite (LAP), irradiating with 365nm ultraviolet light for 30 seconds, and solidifying the solution to obtain sheet hydrogel dressing; or using a stereoscopic light projection 3D printer to prepare hydrogel dressings or stents of different shapes.
Example 5
Dissolving hyaluronic acid in PBS solution to obtain 0.1% solution, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) into the solution after full dissolution, wherein the mass of EDC/NHS is 1/1 and the concentration of EDC in the solution is 0.2%, adjusting the pH of the solution to 4.5, and activating for 40 minutes. Dopamine hydrochloride is prepared into 10% concentration in PBS solution, and the dopamine hydrochloride solution is added into hyaluronic acid solution drop by drop. The mixed solution was placed in a thermostatted shaker and shaken overnight at 20℃in the absence of light. The solution was dialyzed using dialysis bags (pores between 3000 Da) for 24 hours, changing every 6 hours. And freeze-drying to obtain catechol-based hyaluronic acid.
Dissolving the prepared catechol-based hyaluronic acid in 100mM/L MES buffer solution to prepare a solution with the concentration of 0.1%, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) into the solution after the catechol-based hyaluronic acid is fully dissolved, wherein the mass of EDC/NHS is 1/1, the concentration of EDC in the solution is 0.2%, adjusting the pH of the solution to 4.5, and activating for 40 minutes. 2-aminoethyl methacrylate hydrochloride (AEMA) is prepared into a solution with the mass fraction of 10% in an MES solution, and the 2-aminoethyl methacrylate hydrochloride solution is added dropwise into catechol-based hyaluronic acid solution. The mixed solution was placed in a thermostatted shaker and shaken overnight at 20℃in the absence of light. The solution was dialyzed for 24 hours using a dialysis bag (pore 10000 Da) with changing the solution every 6 hours. And freeze-drying to obtain catechol-based photosensitive hyaluronic acid.
Dripping catechol-based photosensitive hyaluronic acid solution with the concentration of 2% into hydrogel molds with different shapes, adding photo-initiator phenyl-2, 4, 6-trimethyl benzoyl lithium phosphite (LAP) with the concentration of 0.5%, irradiating with 365nm ultraviolet light for 20 seconds, and solidifying the solution to obtain a sheet-shaped hydrogel dressing; or using a stereoscopic light projection 3D printer to prepare hydrogel dressings or stents of different shapes.
GD-MA hydrogel material detection
Dissolving raw materials and products in heavy water, scanning a hydrogen spectrum (instrument model: bruker 600 MHz) in a nuclear magnetic resonance spectrometer to obtain absorption peaks of different materials, wherein the absorption peaks of GD-MA are overlapped with dopamine and gelatin, which shows that GD is synthesized by the two raw materials, namely, catechol groups are grafted on side chains of gelatin; characteristic peaks show that the hydrogel is successfully prepared; the GD-MA nuclear magnetic resonance hydrogen spectrum is shown in FIG. 3.
Taking raw materials and products, grinding and tabletting in potassium bromide, and then carrying out Fourier infrared spectrum detection (instrument model: thermo Scientific Nicolet 6700), wherein characteristic peaks show that catechol groups and methacrylate bonds on gelatin side chains are grafted by amide bond reaction. The GD-MA Fourier infrared spectrum results are shown in FIG. 4, with the 1640cm-1 peak illustrating the formation of amide bonds (HNCO). The absorption peak at 1300nm may be changed by the deformation vibration of the stretching vibration methyl group, which is a carbon-carbon double bond, due to the C-H stretching vibration of 3500-3100N-H stretching vibration 1680-1630C=O stretching vibration 1655-1590N-H bending vibration 3100-3000 alkene.
The GD-MA has excellent photosensitive property, can be used for preparing tissue engineering room models with various shapes by using a three-dimensional light projection 3D printer, is shown in a figure 5 (instrument: engineering for life photo-curing biological 3D printer BP 8600), has good printing performance, and can print out precise structures.
As shown in fig. 6, GD-MA was dipped in sodium periodate solution on hydrogel after photo-curing, and the GD-MA hydrogel turned orange yellow, and the contact surface was tightly adhered; after the ferric oxide solution is added into the hydrogel in a dropwise manner, the GD-MA hydrogel turns blue, and the contact surface is tightly adhered. The GD-MA hydrogel is shown to be capable of realizing secondary crosslinking through catechol groups on side chains after photocrosslinking.
As shown in fig. 7, the GD-MA hydrogel was adhered to the tissue tightly by secondary crosslinking, the twisted fold showed tight adhesion of the hydrogel and the tissue, the hydrogel sheets were stacked, the tight adhesion between the hydrogels was shown assembled, immersed in PBS for 30 minutes, and the twisted fold showed tight assembly of the hydrogels.
As shown in FIG. 8, the two molecular weight GD-MA materials were prepared using dialysis bags of different molecular weights, and after hydrogel of different concentrations was prepared, electron microscopy was performed, and it was found that the large molecular weight GD-MA hydrogel prepared using 1000kDa dialysis was larger in pore size, more uniform, and possibly more favorable for cell growth
As shown in fig. 9, in vitro degradation was seen by PBS immersion at 37 ℃, 3w data were recorded, from which it was judged that the rate of high molecular weight GD-MA in vitro degradation was faster, possibly associated with high porosity. (at week 4, the hydrogel was degraded and could not be weighed)
As shown in FIG. 10, the swelling of GD-MA hydrogel was not evident, and the shape was maintained well, as measured by swelling in physiological saline.
As shown in FIGS. 11 and 12, the concentration of GD-MA increases, the hardness of the hydrogel also increases, and the 12% GD-MA material has better elasticity.
As shown in FIGS. 13-15, GD-MA has good biocompatibility.
The hydrogel prepared by the invention has printability and biological adhesion effect; as shown in fig. 16, a millimeter-sized hydrogel tissue engineering chamber was then prepared using the above materials using DLP photo-curing 3D printing technology; performing primary assembly filling on the tissue engineering micro-tissue cultured by the bioreactor to form a micro unit; finally, the biological adhesiveness of the hydrogel is utilized to carry out secondary assembly and splicing on a plurality of tissue engineering room micro units, so that the accurate repair of the defect part can be realized
The foregoing is merely illustrative embodiments of the present invention, and the present invention is not limited thereto, and any changes or substitutions that may be easily contemplated by those skilled in the art within the scope of the present invention should be included in the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the protection scope of the claims.
Claims (7)
1. A secondary crosslinking application method of a hydrogel material with secondary crosslinking characteristics is characterized in that 0.1-1mM/L ferric chloride solution or 0.1-1mM/L sodium periodate solution is prepared, a layer of solution is coated on skin, and then the hydrogel material is stuck on the surface of the skin, so that tight adhesion can be realized; or the two hydrogels are stuck together, and ferric chloride solution or sodium periodate solution is added dropwise to the surfaces of the hydrogels, so that tight adhesion can be realized;
the preparation method of the hydrogel material comprises the following steps:
(1) Dissolving gelatin in PBS solution, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, adjusting the pH of the solution to 4.5-5.5, and activating;
(2) Dissolving dopamine hydrochloride in PBS (phosphate buffer solution), dropwise adding the dopamine hydrochloride solution into the gelatin solution obtained in the step (1), placing the mixed solution in a constant-temperature shaking table, shaking in a dark place, dialyzing, and freeze-drying to obtain catechol gelatin;
(3) Dissolving the catechol gelatin prepared in the step (2) in MES buffer solution, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide into the solution after full dissolution, and performing activation after the pH of the solution is adjusted to 4.5-5.5;
(4) Dissolving 2-aminoethyl methacrylate hydrochloride in MES solution, dropwise adding the 2-aminoethyl methacrylate hydrochloride solution into the catechol-based gelatin solution obtained in the step (3), placing the mixed solution in a constant temperature shaking table, dialyzing after shaking in a dark place, and freeze-drying to obtain catechol-based photosensitive gelatin;
(5) Preparing catechol-based photosensitive gelatin obtained in the step (4) into an aqueous solution with the mass fraction of 5-20%, adding a photoinitiator, then dripping the solution into hydrogel molds with different shapes, and using ultraviolet light irradiation to cure the solution to obtain a sheet-shaped hydrogel dressing; or using a stereoscopic light projection 3D printer to prepare hydrogel dressings or stents of different shapes.
2. The method for using the hydrogel material with the secondary crosslinking property according to claim 1, wherein the mass fraction of the gelatin dissolved in the PBS solution in the step (1) is 0.5% -2%, the mass fraction of the catechol-based gelatin dissolved in the MES buffer solution obtained in the step (2) is 0.5% -2%, and the mass ratio of the dopamine hydrochloride to the gelatin in the mixed solution is 0.2-1:1.
3. the method according to claim 1, wherein the raw material gelatin used in the step (1) is replaced with alginate or hyaluronic acid, the mass fraction of the alginate or hyaluronic acid dissolved in the PBS solution is 0.05% -0.5% and 0.01% -0.3%, respectively, and the mass fraction of the catechol alginate or catechol hyaluronic acid dissolved in the MES buffer solution obtained in the step (2) is 0.05% -0.5% and 0.01% -0.3%, respectively.
4. The method for using the secondary crosslinking of the hydrogel material with the secondary crosslinking property according to claim 1 or 3, wherein the mass ratio of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride added in the step (1) and the step (3) to the N-hydroxysuccinimide is 5:3-1:1, wherein the mass concentration of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in the solution is 0.1-1%, and the activation time of the step (1) and the step (3) is 5-60min.
5. The method for using the hydrogel material with the secondary crosslinking property according to claim 1 or 3, wherein the dopamine hydrochloride in the step (2) is prepared into a PBS solution with a mass concentration of 5% -10%, the temperature of light-proof oscillation is 20-40 ℃, the oscillation time is 5-24 hours, the pore size of a dialysis bag is 3000Da-1000000Da, and the dialysis time is 24-48 hours.
6. The method according to claim 1 or 3, wherein in the step (4), the 2-aminoethylmethacrylate hydrochloride is dissolved in a MES solution having a mass concentration of 5 to 10%, and the mass ratio of the 2-aminoethylmethacrylate hydrochloride to catechol gelatin in the mixed solution is 0.2 to 1:1, the temperature of light-shielding oscillation is 20-40 ℃, the oscillation time is 5-24 hours, the pore space of the dialysis bag is 3000Da-1000000Da, and the dialysis time is 24-48 hours.
7. The method for using the secondary crosslinking of the hydrogel material with the secondary crosslinking property according to claim 1 or 3, wherein 365nm ultraviolet light is adopted in the step (5), the irradiation time is between 5 and 30 seconds, the photoinitiator is LAP or I2959, and the added mass concentration is between 0.1 and 1 percent.
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