CN111548454B

CN111548454B - Preparation method of printable and formable high-strength body temperature release drug hydrogel

Info

Publication number: CN111548454B
Application number: CN202010446940.9A
Authority: CN
Inventors: 李学锋; 舒萌萌; 龙世军; 黄子寒; 陈顺兰; 李捷
Original assignee: Hubei University of Technology
Current assignee: Hubei University of Technology
Priority date: 2020-05-25
Filing date: 2020-05-25
Publication date: 2023-01-20
Anticipated expiration: 2040-05-25
Also published as: CN111548454A

Abstract

The invention discloses a preparation method of printable and formable high-strength body temperature release drug hydrogel, which comprises the steps of firstly preparing chemically crosslinked PNAAMPS hydrogel and grinding the PNAAMPS hydrogel into powder, then adding the PNAAMPS powder into a solution containing NIPAM, AAm monomer, initiator and crosslinking agent, directly pouring the PNAAMPS powder into a glass mold, and polymerizing and forming under the illumination of ultraviolet light. The obtained hydrogel has a unique double-network structure, excellent mechanical strength and toughness, and good environmental responsiveness, and can efficiently load and release small-molecule drugs in a body temperature environment to achieve an antibacterial effect. The invention has simple and easy preparation process, excellent product performance and wide application prospect in the fields of bioengineering, drug controlled release and the like.

Description

Preparation method of printable and formable high-strength body temperature release drug hydrogel

Technical Field

The invention belongs to a high polymer material, and particularly relates to a preparation method of a printable and formable high-strength body temperature release drug hydrogel.

Background

Skin wounds are usually skin tissue injuries caused by external forces. Wound repair, particularly chronic wound repair (such as diabetic skin ulcer), is a worldwide problem to be solved urgently. The bacterial adhesion is easily caused by the exposure of the wound surface caused by the tissue injury, and the defense reaction (inflammatory reaction) of the body can be triggered. The hydrogel dressing is formed by crosslinking a polymer into gel, has the function of creating a moist and bactericidal wound healing environment to temporarily replace skin, but the current hydrogel for repairing the skin wound mainly has the following problems: the hydrogel is poor in mechanical property due to the lack of a strengthening and toughening mechanism design, the wound surface protection effect is poor, and the capability of the wound surface for resisting external force secondary injury is not realized; the wound surface diversity is strong, and the hydrogel dressing can not be formed by wound surface characterization. In order to solve the problems, the comprehensive performance of the ideal skin wound dressing hydrogel needs to cover toughness, wound diversity molding, antibacterial property, good drug release performance and the like.

In view of the above problems, in recent years, many novel antibacterial hydrogels have been developed. Tian et al Tian, R.et al (2018), "simulation of self-Healing Hydrogel with On-detailed biological Activity and stationary biomolecular extraction for induced Skin extraction," Applied Materials&Interfaces 10 (20): 17018-17027 EDTA-Fe ³⁺ Cross-linking Hyaluronic Acid (HA) as a cross-linking agent produces a hydrogel having antibacterial properties. Fe ³⁺ Reversible coordinate bonds are formed with carboxylic acid groups on HA molecular chains, and the hydrogel is endowed with excellent self-healing capability. When the hyaluronic acid is applied to the surface of a wound, the hyaluronidase excreted by bacteria can partially degrade hydrogel and locally release Fe ³⁺ And (5) sterilizing. The hydrogel is simple in preparation process, has good antibacterial capacity, but is poor in mechanical property and difficult to apply in practice. Gan et al, gan, d, et al, (2018), "muscle-induced contact-active antibacterial hydrogel with high cell affinity, toughnesss, and reproducibility". Advanced Functional Materials 29 (1): 1805964. Hydrogels with contact enhanced antibacterial properties were prepared by Mussel-like strategies. By combining an antimicrobial polymer comprising 2- (dimethylamino) ethyl methacrylate (DMAEMA) and a quaternized shellThe polysaccharide (QCS) is incorporated into a polyacrylic acid matrix. The presence of doubly-bonded dopamine (MADA) enhances the contact of the bacteria with the hydrogel, which then effectively kills the bacteria with the antimicrobial components DMAEMA and QCS in the hydrogel. MADA allows hydrogels to have higher toughness and compression/tension recoverability by incorporating non-covalent bonds into the hydrogel. In addition, the catechol functional groups on the MADA also have the effect of increasing cell/tissue affinity, so that the hydrogel has good biocompatibility and cell/tissue adhesion. The hydrogel has good antibacterial property and biocompatibility, but the dopamine compound with the catechol structure is easy to be converted into the quinoid structure, so that the performance is unstable, and the application of the hydrogel in the biological environment with a complex shape is limited due to the limitation of a forming method. Zhao et al Zhao, x., et al (2017) "Antibacterial anti-oxidant active capable hydrogel as selected-healing side driving with a high-viscosity and adhesive for cosmetic side driving," Biomaterials 122-47. Polyethylene glycol-co-poly (glycerol-sebacic acid) functionalized with aromatic aldehyde group as a cross-linking agent was subjected to dynamic chemical bond cross-linking with quaternized chitosan-g-polyaniline (QCSP), to prepare an injectable hydrogel dressing having self-healing, high adhesive force. The hydrogel can rapidly seal wounds of any shapes by in-situ gelling and tissue adhesion performance, and simultaneously, the hemostatic performance and the antibacterial performance of the hydrogel can rapidly stop bleeding of the wounds and prevent wound infection. Based on the healing promoting ability of the chitosan component in QCSP, the hydrogel has potential as a bioactive dressing in wound healing applications. However, the synthesis steps of the hydrogel are complicated, hydrochloric acid is used in the gelling injection, hidden danger of wound application is increased, in-situ gelling is performed after injection in a wound area, the hydrogel is suitable for hemostasis and sealing of minimally invasive endoscopic surgery, the mechanical property of the hydrogel formed by curing the glue is low, and the application requirement of bonding larger wound wounds cannot be met.

Previous researches show that introducing functional groups, loading drugs and the like are effective strategies for endowing hydrogel with antibacterial property. Most of the antibacterial hydrogels have the disadvantages of poor mechanical properties, difficult free forming, poor biocompatibility and the like. The preparation of antibacterial hydrogel which can be freely formed and has high mechanical properties has become an urgent and important work.

Disclosure of Invention

The invention aims to solve the technical problems and provides a preparation method of the printable and formable high-strength body temperature release drug hydrogel, which has the advantages of simple process, easy operation and control, easily obtained raw materials, lower cost and shorter period.

The technical scheme comprises the following specific steps:

a preparation method of printable and formable high-strength body temperature release drug hydrogel comprises the following specific steps:

1) Preparing a chemically cross-linked poly 2-acrylamido-2-methylpropanesulfonic acid (PNaAMPS) hydrogel;

2) Drying the PNAAMPS hydrogel prepared in the step (1) in a vacuum drying oven to constant weight, grinding and sieving to obtain PNAAMPS powder;

3) Adding PNAAMPS powder, N-isopropylacrylamide (NIPAM), acrylamide (AAm), a cross-linking agent and an initiator into deionized water, and stirring to dissolve to obtain a semitransparent solution;

4) And (4) putting the solution obtained in the step (3) into a mould, and polymerizing and crosslinking the monomers to obtain the PNAAMPS/P (NIPAM-co-AAm) hydrogel.

Preferably, the step (1) of preparing the chemically crosslinked PNaAMPS hydrogel comprises the steps of: adding AMPS, naOH, N-dimethyl bisacrylamide (MBAA) and 2-Ketoglutaric Acid (KA) into deionized water, stirring to dissolve to obtain a transparent solution, filling the transparent solution into a mold consisting of a glass sheet and a silica gel gasket, and performing photopolymerization under the illumination of an ultraviolet lamp to obtain the PNAAMPS hydrogel.

Preferably, the resulting clear solution has a molar concentration of 1mol/L monomer AMPS, 1mol/L monomer NaOH, 0.01mol/L monomer MBAA, and 0.001mol/L monomer KA.

Preferably, the particle size of the PNaAMPS powder obtained in step (2) is 10 to 200 μm.

Preferably, the temperature for vacuum drying in step (2) is 80 ℃.

Preferably, MBAA is used as a cross-linking agent and KA is used as a photoinitiator in the step (3), in the solution obtained in the step (3), the mass concentration of PNAAMPS is 0.015-0.035 mg/mL, the molar concentration of NIPAM is 1-4 mol/L, the molar concentration of AAm is 1-4 mol/L, and the molar concentration of MBAA is 0.001mol/L

mol/L, the molar concentration of KA is 0.001mol/L.

Preferably, in the step (1) and the step (4), the conditions for initiating polymerization crosslinking of the monomers are light irradiation for 7 to 10 hours at a position of 10 to 30cm under a high-pressure mercury lamp with power of 200 to 500W.

Preferably, in the step (4), during the polymerization reaction, the periphery of the mold is cooled by circulating water, and the temperature in the mold is controlled to be 10-20 ℃.

Preferably, when the particle concentration of the PNaAMPS in the step (3) is 0.030 to 0.035g/mL, the viscosity of the obtained solution can satisfy the requirement of realizing 3D printing free forming by directly using an injector.

The invention also aims to provide application of the high-strength body temperature release drug hydrogel obtained by the preparation method in wound repair dressing, and the obtained PNAAMPS/P (NIPAM-co-AAm) hydrogel is completely immersed in a drug solution to obtain drug-loaded PNAAMPS/P (NIPAM-co-AAm) hydrogel.

According to the invention, the NIPAM monomer with temperature sensitivity is introduced into the second network of the double-network hydrogel, on the premise of keeping the excellent mechanical property of the double-network hydrogel, the temperature sensitivity characteristic is given to the hydrogel, and the hydrophilicity and hydrophobicity of the hydrogel can be regulated and controlled by changing the temperature, so that the further functional application of the hydrogel is realized. And the micromolecular antibacterial agent (such as crystal violet CV) introduced by the soaking method has good hydrophilicity. The PNAAMPS/P (NIPAM-co-AAm)/CV hydrogel is placed in a body temperature environment of about 37 ℃ (the temperature is higher than the low critical solution temperature of the hydrogel), PNIPAM chain segments in the hydrogel network are agglomerated to form a hydrophobic spherical structure, the hydrogel network becomes more compact, the hydrophobicity is enhanced, the hydrogel can be adhered to the surface of biological tissues, partial water in the network is discharged along with the size shrinkage of the hydrogel, partial water-soluble drug molecules are released along with the release of the water-soluble drug molecules, and the water-soluble drug molecules react with bacteria on the surface of the tissues, so that the aim of sterilization is fulfilled.

The novel double-network hydrogel is prepared by drying and grinding the pre-polymerized gel into powder, adding the powder into a second double-network monomer solution, and then curing and forming, so that the problem that the mechanical property is influenced due to uneven distribution of NIPAM monomer hydrophilic and hydrophobic properties in a first network of a massive prepolymer caused by uneven distribution of NIPAM monomer hydrophilic and hydrophobic properties in a reaction process when the temperature-sensitive hydrogel is prepared by a direct prepolymer soaking method used in the conventional double-network hydrogel is solved; the traditional one-pot method for preparing the double-network hydrogel can not select the polymerization design of double monomers or multiple monomers in the system. In the hydrogel preparation process, NIPAM and AAm are copolymerized into P (NIPAM-co-AAm) molecular chains through free radical polymerization, and the polymer molecular chains are mutually interpenetrated with a large amount of micro-particle powdery PNAAMPS networks. On one hand, the two networks are mutually inserted, and the rigid PNAAMPS network is further broken to dissipate energy when deformation occurs; on the other hand, the micro-particle powdery PNAAMPS network can be used as a physical cross-linking agent of a polymer network, chain sliding is generated in the deformation process to adjust the molecular weight of a cross-linking point, and the stress distribution in the gel is balanced, so that the double-network hydrogel shows excellent mechanical properties. Meanwhile, as the hydrogel is solidified and molded when the second network is polymerized, the monomer solution before polymerization contains water-absorbing swelling PNAAMPS particles, the viscosity is moderate, a viscosity regulator (such as fumed silica) is not required to be added to regulate the viscosity, and an injector can be used for extruding lines, so that the free molding of the hydrogel can be realized, the problem of non-uniformity of samples caused by doping inorganic filler is avoided, and the limitation of the shape and the size of the hydrogel in practical application is overcome.

The hydrogel prepared by the invention has excellent mechanical properties and good environmental responsiveness. The preparation process is simple and easy to control, and the prepared hydrogel has a uniform structure, has the advantages of free forming, high strength, antibacterial property, environmental responsiveness and the like, and is a common method for preparing the printable and formable high-strength body temperature release medicinal antibacterial hydrogel.

Compared with the prior art, the invention has the following advantages and remarkable progress:

1) The preparation process is simple and easy to implement, good in controllability, simple and convenient in process conditions, low in production cost, easy to obtain raw materials, stable in product performance and capable of realizing large-scale industrial application.

2) The invention constructs a unique structure of mutual interpenetration of double polymer networks and constructs double-network hydrogel with an effective energy dissipation mechanism. When the deformation occurs, the rigid first heavy network is broken to dissipate energy, and the fragments of the network can be used as cross-linking points of the second heavy network to balance internal stress through chain sliding, so that the energy is further dissipated. The hydrogel prepared by the unique network structure has excellent mechanical properties.

3) And a functional monomer NIPAM is introduced, so that the hydrogel has good environmental responsiveness. In a body temperature environment, the hydrogel can be adhered to the surface of a tissue and quickly releases drug molecules, so that the aim of antibiosis is fulfilled, and the hydrogel has application potential in the fields of bioengineering, drug controlled release and the like.

4) The first double-network is dried and ground into powder and then added into the monomer solution of the second double-network, so that the risk of uncertain molar ratio of double-network monomers caused by a soaking method for preparing the traditional double-network hydrogel is effectively avoided, and the preparation time is greatly shortened. Under a proper proportion, the viscosity of the second-network monomer solution is moderate, and the line is extruded by an injector and then is polymerized by illumination, so that various complex shapes can be realized, and the application occasions of the hydrogel are greatly widened.

Drawings

FIG. 1 is a schematic diagram of the network structure in a PNAAMPS/P (NIPAM-co-AAm) hydrogel;

FIG. 2 is a diagram showing the mechanism of inhibition of PNAAMPS/P (NIPAM-co-AAm)/CV in a body temperature environment.

Wherein:

Detailed Description

Example 1

Step 1): 2.0725g AMPS (1 mol/L), 0.4g NaOH (1 mol/L), 0.0616g MBAA (0.04 mol/L) and 0.0015g KA (0.001 mol/L) are respectively weighed into a beaker, 10mL deionized water is added, and the mixture is uniformly stirred to obtain a transparent solution. And pouring the solution into a glass mold, and placing the glass mold under a high-pressure mercury lamp with the power of 200-500W for illumination at a position of 10-30 cm for 7-10 hours to obtain the PNAAMPS hydrogel.

Step 2): and (2) drying the hydrogel prepared in the step (1) in a vacuum drying oven at 80 ℃ to constant weight, and grinding and sieving to obtain the PNAAMPS powder with the particle size of 10-200 mu m.

And step 3): 0.15g of PNAAMPS (0.015 g/mL), 0.5658g of NIPAM (0.5 mol/L), 2.4878g of AAm (3.5 mol/L), 0.0154g of MBAA (0.01 mol/L) and 0.0015g of KA (0.001 mol/L) are weighed into a beaker, 10mL of deionized water is added, and the mixture is stirred uniformly to obtain a semitransparent solution.

And step 4): and (4) pouring the solution obtained in the step (3) into a glass mold, and placing the glass mold under a high-pressure mercury lamp with the power of 200-500W for illumination for 7-10 hours at a position of 10-30 cm to obtain the PNAAMPS/P (NIPAM-co-AAm) hydrogel.

Step 5): the hydrogel obtained in step (4) was cut into a disk shape having a diameter of 10mm, the mass was measured, and the disk shape was placed in 20mL of CV aqueous solution having a mass concentration of 0.54g/L and left at 20 ℃ for 12 hours.

Step 6): and (4) taking out the wafer sample in the CV aqueous solution in the step (5), and measuring the absorbance value of the CV aqueous solution after gel adsorption by using an ultraviolet spectrophotometer.

Step 7): and (4) sucking the water on the surface of the wafer sample taken out in the step (6) to be dry, putting the wafer sample into 20mL of deionized water with the temperature of 37 ℃, and standing the wafer sample at the temperature of 37 ℃ for 3 hours.

Step 8): and (4) taking out the wafer sample in the step (7), and measuring the absorbance value of the water solution after the CV is released from the gel by using an ultraviolet spectrophotometer.

The tensile strength of the high-strength body temperature release drug-containing antibacterial hydrogel obtained in the embodiment at room temperature is 1.36MPa, and the elongation at break is 634%. From the calibration curve, the CV release efficiency per gram of gel at 37 ℃ was calculated to be 38.43%.

Example 2

Step 3): 0.15g of PNAAMPS (0.015 g/mL), 1.1316g of NIPAM (1 mol/L), 2.1324g of AAm (3 mol/L), 0.0154g of MBAA (0.01 mol/L) and 0.0015g of KA (0.001 mol/L) are weighed into a beaker, 10mL of deionized water is added, and the mixture is stirred uniformly to obtain a semitransparent solution.

And step 4): and (4) pouring the solution obtained in the step (3) into a glass mold, and placing the glass mold under a high-pressure mercury lamp with the power of 200-500W for illumination at a position of 10-30 cm for 7-10 hours to obtain the PNAAMPS/P (NIPAM-co-AAm) hydrogel.

Step 5): the hydrogel obtained in step (4) was cut into a disk shape having a diameter of 10mm, the mass was measured, and the disk was put into 20mL of CV aqueous solution having a mass concentration of 0.54g/L and left at 20 ℃ for 12 hours.

The experiment shows that the tensile strength of the high-strength body temperature release drug antibacterial hydrogel obtained in the embodiment is 1.15MPa under the condition of room temperature, and the elongation at break is 521%. From the calibration curve, the CV release efficiency per gram of gel at 37 ℃ was calculated to be 43.04%.

Example 3

Step 3): 0.15g of PNAAMPS (0.015 g/mL), 1.6974g of NIPAM (1.5 mol/L), 1.7770g of AAm (2.5 mol/L), 0.0154g of MBAA (0.01 mol/L) and 0.0015g of KA (0.001 mol/L) are weighed into a beaker, 10mL of deionized water is added, and the mixture is stirred uniformly to obtain a translucent solution.

Step 4): and (4) pouring the solution obtained in the step (3) into a glass mold, and placing the glass mold under a high-pressure mercury lamp with the power of 200-500W for illumination for 7-10 hours at a position of 10-30 cm to obtain the PNAAMPS/P (NIPAM-co-AAm) hydrogel.

The tensile strength of the high-strength body temperature release drug-containing antibacterial hydrogel obtained in the embodiment at room temperature is 0.98MPa, and the elongation at break is 458%. From the calibration curve, the CV release efficiency per gram of gel at 37 ℃ was calculated to be 48.27%.

Example 4

Step 3): 0.15g of PNAAMPS (0.015 g/mL), 2.2632g of NIPAM (2 mol/L), 1.4216g of AAm (2 mol/L), 0.0154g of MBAA (0.01 mol/L) and 0.0015g of KA (0.001 mol/L) are weighed into a beaker, 10mL of deionized water is added, and the mixture is stirred uniformly to obtain a semitransparent solution.

And step 5): the hydrogel obtained in step (4) was cut into a disk shape having a diameter of 10mm, the mass was measured, and the disk was put into 20mL of CV aqueous solution having a mass concentration of 0.54g/L and left at 20 ℃ for 12 hours.

According to the experiment, the tensile strength of the high-strength body temperature release drug antibacterial hydrogel obtained in the embodiment under the room temperature condition is 0.87MPa, and the elongation at break is 394%. From the calibration curve, the CV release efficiency per gram of gel at 37 ℃ was calculated to be 52.89%.

Example 5

Step 3): 0.15g of PNAAMPS (0.015 g/mL), 2.8290g of NIPAM (2.5 mol/L), 1.0662g of AAm (1.5 mol/L), 0.0154g of MBAA (0.01 mol/L) and 0.0015g of KA (0.001 mol/L) are weighed into a beaker, 10mL of deionized water is added, and the mixture is stirred uniformly to obtain a translucent solution.

Step 6): and (6) taking out the wafer sample in the CV aqueous solution obtained in the step (5), and measuring the absorbance value of the CV aqueous solution after gel adsorption by using an ultraviolet spectrophotometer.

Step 7): and (4) sucking the water on the surface of the wafer sample taken out in the step (6), putting the wafer sample into 20mL of deionized water with the temperature of 37 ℃, and standing the wafer sample at 37 ℃ for 3 hours.

According to the experiment, the tensile strength of the high-strength body temperature release drug antibacterial hydrogel obtained in the embodiment at room temperature is 0.72MPa, and the elongation at break is 350%. From the calibration curve, the CV release efficiency per gram of gel at 37 ℃ was calculated to be 60.04%.

Example 6

Step 3): 0.30g of PNAAMPS (0.030 g/mL), 2.8290g of NIPAM (2.5 mol/L), 1.0662g of AAm (1.5 mol/L), 0.0154g of MBAA (0.01 mol/L) and 0.0015g of KA (0.001 mol/L) are weighed into a beaker, 10mL of deionized water is added, and the mixture is stirred uniformly to obtain a translucent solution.

Step 4): extruding the solution obtained in the step (3) into lines through a syringe, and printing the lines into a wafer shape with the diameter of 10mm in a glass mold. Sealing by a glass sheet and a silica gel gasket, and then placing under a high-pressure mercury lamp with the power of 200-500W for illumination at a position of 10-30 cm for 7-10 hours to obtain a PNAAMPS/P (NIPAM-co-AAm) wafer-shaped hydrogel sample, wherein the shape of the obtained sample is better consistent with the printing shape.

Step 5): the mass of the disc-shaped sample printed in step (4) was measured and placed in 20mL of CV aqueous solution having a mass concentration of 0.54g/L and left at 20 ℃ for 12 hours.

Step 8): and (5) taking out the wafer sample in the step (7), and measuring the absorbance value of the aqueous solution after the gel releases the CV by using an ultraviolet spectrophotometer.

According to the experiment, the tensile strength of the high-strength body temperature release drug antibacterial hydrogel obtained in the embodiment at room temperature is 0.64MPa, and the elongation at break is 327%. From the calibration curve, the CV release efficiency per gram of gel at 37 ℃ was calculated to be 55.36%. The hydrogel sample obtained by printing in the experiment has a stable three-dimensional structure.

Comparative example 1

Step 2): and (2) drying the hydrogel prepared in the step (1) in a vacuum drying oven at 80 ℃ to constant weight, grinding and sieving to obtain the PNAAMPS powder with the particle size of 10-200 mu m.

Step 3): 0.15g of PNAAMPS (0.015 g/mL), 2.8432g of AAm (4 mol/L), 0.0154g of MBAA (0.01 mol/L) and 0.0015g of KA (0.001 mol/L) are weighed into a beaker, 10mL of deionized water is added, and the mixture is stirred uniformly to obtain a semitransparent solution.

Step 4): and (4) pouring the solution obtained in the step (3) into a glass mold, and placing the glass mold under a high-pressure mercury lamp with the power of 200-500W for illumination for 7-10 hours at a position of 10-30 cm to obtain the PNAAMPS/AAm hydrogel.

According to the experiment, the tensile strength of the double-network hydrogel obtained by the comparative example is 1.78MPa, and the elongation at break is 970%. From the calibration curve, the CV release efficiency per gram of gel at 37 ℃ was calculated to be 30.15%.

Comparative example 2

And step 3): 0.15g of PNAAMPS (0.015 g/mL), 2.8290g of NIPAM (2.5 mol/L), 0.0154g of MBAA (0.01 mol/L) and 0.0015g of KA (0.001 mol/L) are weighed into a beaker, 10mL of deionized water is added, and the mixture is stirred uniformly to obtain a translucent solution.

Step 4): and (4) pouring the solution obtained in the step (3) into a glass mold, and placing the glass mold under a high-pressure mercury lamp with the power of 200-500W for illumination at a position of 10-30 cm for 7-10 hours to obtain the PNAAMPS/PNIPAM hydrogel. For determining mechanical strength.

Step 5): and (5) cutting the PNAAMPS/PNIPAM hydrogel prepared in the step (4) by using a circular sample knife to obtain a circular sample with the diameter of 10mm, and using the circular sample for CV adsorption and release experiments.

Step 6): the mass of the disc-shaped sample obtained in step (5) was measured, and it was put into 20mL of CV aqueous solution having a mass concentration of 0.54g/L and left at 20 ℃ for 12 hours.

Step 7): and (5) taking out the wafer sample in the CV aqueous solution in the step (6), and measuring the absorbance value of the CV aqueous solution after gel adsorption by using an ultraviolet spectrophotometer.

Step 8): and (4) sucking the water on the surface of the wafer sample taken out in the step (7) to be dry, putting the wafer sample into 20mL of deionized water with the temperature of 37 ℃, and standing the wafer sample at the temperature of 37 ℃ for 3 hours.

Step 9): and (5) taking out the wafer sample in the step (8), and measuring the absorbance value of the water solution after the CV is released from the gel by using an ultraviolet spectrophotometer.

The experiment shows that the tensile strength of the double-network hydrogel obtained in the comparative example is 0.33MPa and the elongation at break is 465 percent under the room temperature condition. From the calibration curve, the CV release efficiency per gram of gel at 37 ℃ can be calculated to be 74.32%.

Comparative example 3

Step 2): 28.290g of NIPAM (2.5 mol/L), 10.662g of AAm (1.5 mol/L), 0.0015g of MBAA (0.0001 mol/L) and 0.0015g of KA (0.0001 mol/L) are weighed into a beaker, 100mL of deionized water is added, and the mixture is stirred uniformly to obtain a translucent solution.

And step 3): and (3) putting the hydrogel obtained in the step (1) into the solution obtained in the step (2), soaking for 24 hours in the dark at 4 ℃, taking out the hydrogel, sucking the surface moisture by using filter paper, putting the hydrogel into a glass mold, and putting the glass mold under a high-pressure mercury lamp with the power of 200-500W for illumination for 7-10 hours at a position of 10-30 cm to obtain the PNAAMPS/P (NIPAM-co-AAm) hydrogel.

Step 4): and (3) cutting the PNAAMPS/PNIPAM hydrogel prepared in the step (3) by using a circular sample knife to obtain a circular sample with the diameter of 10mm, and using the circular sample for CV adsorption and release experiments.

Step 5): the mass of the disc-shaped sample obtained in step (4) was measured, and it was put into 20mL of CV aqueous solution having a mass concentration of 0.54g/L and left at 20 ℃ for 12 hours.

The experiment shows that the tensile strength of the double-network hydrogel obtained in the comparative example is 0.012MPa at room temperature, and the elongation at break is 540%. From the calibration curve, the CV release efficiency per gram of gel at 37 ℃ was calculated to be 47.62%.

The tensile strength, elongation at break and CV release efficiency at 37 ℃ for 3 hours of the hydrogels of the above examples and comparative examples are shown in table 1 below:

table 1: tensile strength, elongation at break and CV Release efficiency of hydrogel at 37 ℃ for 3 hours

As can be seen from the data in the table:

examples 1 to 5 are different PNaAMPS/P (NIPAM-co-AAm) hydrogels prepared by pre-polymerizing gel milling while changing the molar ratio of the NIPAM in the mixed solution of the NIPAM/AAm, comparative example 1 is a prepared PNaAMPS/PAAm hydrogel, comparative example 2 is a prepared PNaAMPS/PNIPAM hydrogel, and comparative example 3 is a PNaAMPS/P (NIPAM-co-AAm) double network hydrogel prepared by a direct immersion method.

As can be seen from the tensile data of examples 1 to 5 and comparative example 1 in the table, as the content of NIPAM in the total monomers in the secondary network increases, the tensile strength of the hydrogel decreases from 1.78MPa to 0.72MPa, and the elongation at break also decreases from 970% to 350%. This is because NIPAM has lower hydrophilicity than AAm, and as the content of NIPAM increases, the hydrophilicity of the copolymer decreases gradually, and the polymer network becomes tighter, restricting the movement of molecular chains, and thus the elongation at break decreases. As can be seen from the adsorption and release experiments of CV of examples 1 to 5, as the content of NIPAM in the second monomer increases, the higher the CV release efficiency of hydrogel per unit mass at 37 ℃ within 3 hours, i.e. the higher the NIPAM content, the more rapidly the hydrogel can release CV molecules in a body temperature environment. The gel was placed in the CV solution again at 20 ℃ and the hydrogel could re-adsorb the CV. This indicates that the reversible temperature sensitive properties brought about by the introduction of NIPAM provide hydrogel with the ability to rapidly release drugs and repeatedly load drugs in a biological environment. As can be seen from examples 1 to 5 and comparative example 1, the PNaAMPS/PAAm double-network hydrogel has more excellent mechanical properties, but the CV release efficiency is low because the hydrogel only reaches the CV concentration balance between the inside and the outside of the hydrogel during releasing CV. And the PNAAMPS/P (NIPAM-co-AAm) hydrogel releases more CV molecules while the hydrogel shrinks and dehydrates due to the hydrophobic property of the PNAAMPS/P hydrogel. As can be seen from example 5 and comparative example 2, the PNaAMPS/PNIPAM hydrogel has a higher CV release efficiency because it has a higher proportion of hydrophobic moieties in the network, exhibits greater temperature sensitivity, but has a lower strength, limiting its further use. It can be seen from example 5 and comparative example 3 that the double-network hydrogel prepared by the soaking method has low mechanical strength, low CV release efficiency and poor temperature sensitivity, which is caused by the fact that the NIPAM monomer generates hydrophilic-hydrophobic transition due to the temperature change of the solution in the soaking process, resulting in the nonuniformity of the hydrogel structure. In example 5, the second heavy network was directly polymerized by adding a monomer solution after the first heavy network was ground into powder, so that a uniform and stable bulk sample could be prepared, which is more suitable for preparing temperature-sensitive double-network hydrogel.

Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. A preparation method of printable and formable high-strength body temperature release drug hydrogel is characterized by comprising the following specific steps:

(1) Preparing a chemically cross-linked poly 2-acrylamide-2-methyl sodium propane sulfonate (referred to as PNAAMPS) hydrogel;

(2) Drying the PNAAMPS hydrogel prepared in the step (1) in a vacuum drying oven to constant weight, grinding and sieving to obtain PNAAMPS powder;

(3) Adding PNAAMPS powder, N-isopropylacrylamide (NIPAM), acrylamide (AAm), a cross-linking agent N, N-Methylenebisacrylamide (MBAA) and an initiator 2-oxoglutaric acid (KA) into deionized water, and stirring to dissolve to obtain a semitransparent solution;

(4) Putting the solution in the step (3) into a mold to polymerize and crosslink the monomers, and in the step (4), cooling the periphery of the mold by using circulating water during polymerization reaction, wherein the temperature of the mold is controlled within 10 to 20 DEG ^o C, obtaining PNAAMPS/P (NIPAM-co-AAm) hydrogels.

2. The method of preparing according to claim 1, wherein the step of preparing the chemically cross-linked PNaAMPS hydrogel in the step (1) is: adding 2-acrylamide-2-methylpropanesulfonic Acid (AMPS), naOH, MBAA and KA into deionized water, stirring and dissolving to obtain a transparent solution, pouring the transparent solution into a mold consisting of a glass sheet and a silica gel gasket, and carrying out photopolymerization under the irradiation of an ultraviolet lamp to obtain the PNAAMPS hydrogel.

3. The method according to claim 2, wherein the transparent solution is obtained in which the molar concentration of AMPS monomer is 1mol/L, the molar concentration of NaOH is 1mol/L, the molar concentration of MBAA is 0.01mol/L, and the molar concentration of KA is 0.001mol/L.

4. The method according to claim 1, wherein the particle size of the PNAAMPS powder obtained in step (2) is 10 to 200 μm.

5. The method according to claim 1, wherein the temperature of the vacuum drying in the step (2) is 80 ℃.

6. The preparation method according to claim 1, wherein in the solution obtained in step (3), the mass concentration of PNAAMPS is 0.015 to 0.035mg/mL, the molar concentration of NIPAM is 1 to 4mol/L, the molar concentration of AAm is 1 to 4mol/L, the molar concentration of MBAA is 0.001mol/L, and the molar concentration of KA is 0.001mol/L.

7. The process according to claim 1, wherein in the steps (1) and (4), the conditions for initiating the polymerization and crosslinking of the monomer are light irradiation at 10 to 30cm for 7 to 10 hours under a high-pressure mercury lamp with a power of 200 to 500W.

8. The preparation method according to claim 1, wherein when the concentration of the particles of the PNAAMPS in the step (3) is 0.030 to 0.035g/mL, the viscosity of the obtained solution can meet the requirement of realizing 3D printing free forming by directly adopting an injector.

9. The application of the high-strength body temperature release medicinal hydrogel obtained by the preparation method of any one of claims 1 to 8 in wound repair dressing is characterized in that the obtained PNAAMPS/P (NIPAM-cothe-AAm) hydrogel is completely immersed into the drug solution to obtain drug-loaded PNAAMPS/P (NIPAM-co-AAm) hydrogel.