CN114870079A - Carbon quantum dot-based antibacterial and bone repair promoting hydrogel and preparation method and application thereof - Google Patents
Carbon quantum dot-based antibacterial and bone repair promoting hydrogel and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides an antibacterial and bone repair promoting hydrogel based on carbon quantum dots and a preparation method and application thereof. The composite hydrogel comprises Arg-CQD, HA-CHO (oxidized hyaluronic acid) and GelMA (methacrylic acylated gelatin), and the CQD/HA/GelMA composite hydrogel HAs good biocompatibility, can respond to an infectious bone injury microenvironment to release Arg-CQD nanoparticles, can continuously sterilize and promote bone tissue repair, and can be used as an excellent infectious bone injury repair material for bone tissue engineering.
Description
Technical Field
The invention belongs to the technology in the field of biomedical materials, and particularly relates to an antibacterial and bone repair promoting hydrogel based on carbon quantum dots, and a preparation method and application thereof.
Background
Infection is a major cause of bone implant failure. Orthopedic implant related infections are mainly caused by staphylococcus aureus and can delay the healing process, resulting in bone loss, requiring extensive surgical intervention and long-term antibiotic treatment. However, repeated antibiotic treatment increases the likelihood of resistance (40% of pathogenic staphylococcus aureus is methicillin-resistant). These infections often lead to implant failure, require replacement of the implant, and result in chronic and/or recurrent disease. Severe infections, in addition to causing pain and economic loss in further treatment, may also lead to amputation or fatal sepsis. Current optimization studies of bone implants focus mainly on surface modification or by altering topological features to promote stem cell differentiation and induce bone regeneration.
Although various materials can achieve the purpose of removing bacteria by generating ROS (reactive oxygen species), the generated ROS cannot identify bacteria and cells, so that the generated ROS can damage surrounding tissues while killing the bacteria, thereby limiting the further application of the materials in infectious bone injury repair.
Therefore, it is important to develop a material that can both eliminate bacteria and promote bone regeneration while protecting tissue from damage.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an antibacterial and bone repair promotion hydrogel (CQD/HA/GelMA composite hydrogel) based on carbon quantum dots, a preparation method and an application thereof, wherein the antibacterial and bone repair promotion hydrogel based on the carbon quantum dots comprises Arg-CQD (arginine carbon quantum dots), HA-CHO (oxidized hyaluronic acid) and GelMA (methacrylated gelatin), can respond to an acidic bone injury microenvironment to release Arg-CQD, remove bacteria and promote bone tissue repair, and can be used for bone tissue engineering as an excellent infectious bone injury repair material.
The purpose of the invention is realized by the following technical scheme:
the invention aims to provide an antibacterial and bone repair promoting hydrogel based on carbon quantum dots, which comprises the following components: Arg-CQD (arginine carbon quantum dot), HA-CHO (oxidized hyaluronic acid) and GelMA (methacrylated gelatin).
In one embodiment of the invention, the Arg-CQD is a nanoparticle with a particle size of 3-20 nm.
In one embodiment of the invention, the concentration of the Arg-CQD nanoparticles is 2-20 mg/mL.
In one embodiment of the invention, the HA-CHO concentration is 10-30% (w/v).
The second purpose of the invention is to provide a preparation method of the carbon quantum dot-based antibacterial and bone repair-promoting hydrogel, which comprises the following steps: adding Arg-CQD and HA-CHO into a GelMA solution, dissolving, and then carrying out a photo-crosslinking reaction to prepare the carbon quantum dot-based antibacterial and bone repair promotion hydrogel (namely the CQD/HA/GelMA composite hydrogel).
Further, the preparation method of the carbon quantum dot-based antibacterial and bone repair promotion hydrogel comprises the following steps: (1) calcining arginine powder at 200-400 ℃ for 3-6 h, naturally cooling to room temperature, dissolving the calcined arginine powder in ultrapure water, performing ultrasonic treatment for 30-90 min, centrifuging at 10000-15000 rpm for 30-60 min, adding the supernatant into a dialysis bag with MWCO of 1000Da, dialyzing in the ultrapure water for 24-72 h, and finally performing freeze drying to obtain Arg-CQD nanoparticles;
(2) dissolving HA in deionized water, adding a strong oxidant, stirring at room temperature for 2-6 h, adding ethylene glycol to terminate the reaction, adding the reaction solution into a dialysis bag with MWCO of 8000Da, dialyzing in the deionized water for 72-144 h, and finally freeze-drying to obtain HA-CHO;
(3) and (2) adding the Arg-CQD nano-particles prepared in the step (1) and HA-CHO prepared in the step (2) into GelMA, fully dissolving under a heating condition, and crosslinking by ultraviolet light or blue light to prepare CQD/HA/GelMA composite hydrogel.
In one embodiment of the present invention, the Arg-CQD is prepared by the following method: and calcining and cooling arginine powder, dissolving the arginine powder in a solvent, centrifuging the solution, and freeze-drying the centrifuged supernatant to obtain the Arg-CQD.
In one embodiment of the invention, the calcination temperature is 200-400 ℃, and the calcination time is 3-6 h.
In one embodiment of the invention, the HA-CHO is prepared by the following method: and adding a strong oxidant into the HA aqueous solution, uniformly mixing, then adding ethylene glycol to terminate the reaction, and freeze-drying the reaction solution to obtain the HA-CHO.
In one embodiment of the invention, the mass ratio of the HA to the strong oxidant is 1: 1-5: 1.
In one embodiment of the invention, the strong oxidizing agent is selected from sodium periodate or potassium permanganate.
The third purpose of the invention is to provide the application of the carbon quantum dot-based antibacterial and bone repair promotion hydrogel in the preparation of infectious bone injury repair medicines.
Compared with the prior art, the invention has the advantages that:
(1) the CQD/HA/GelMA composite hydrogel can respond to an acidic microenvironment at an infectious bone injury part to release Arg-CQD nanoparticles, and is partially degraded.
(2) The Arg-CQD nanoparticles released in response to the infectious bone injury microenvironment can improve the ROS level in bacteria and cells and eliminate bacteria at the injured parts.
(3) The Arg-CQD nanoparticles can improve the expression of intracellular antioxidase and protect cells from being damaged by excessive ROS.
(4) The Arg-CQD nanoparticles can improve the expression of IL-10 (Interleukin-10) in cells, induce macrophage M2 polarization and promote bone tissue repair.
(5) The CQD/HA/GelMA composite hydrogel HAs good biocompatibility, can respond to an infectious bone injury microenvironment to release Arg-CQD nanoparticles, continuously sterilize and promote osteogenic differentiation, and can be used as an excellent infectious bone injury repair material for bone tissue engineering.
Drawings
FIG. 1 is a TEM image of Arg-CQD nanoparticles of example 1 of the present invention;
FIG. 2 is an infrared spectrum of HA-CHO in example 1 of the present invention;
FIG. 3 is an SEM photograph of the CQD/HA/GelMA composite hydrogel in example 2 of the present invention;
FIG. 4 is a graph of the compressive strength of a hydrogel in example 2 of the present invention;
FIG. 5 is a graph of the release of Arg-CQD nanoparticles from the CQD/HA/GelMA composite material in example 3 of the present invention;
FIG. 6 shows that CQD/HA/GelMA can significantly kill bacteria in example 3 of the present invention;
FIG. 7 shows that CQD/HA/GelMA promotes the production of a large amount of calcium deposition in cells in example 3 of the present invention.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to the accompanying drawings and specific embodiments.
Example 1
The preparation method of the CQD/HA/GelMA composite hydrogel of the embodiment includes the following steps:
s11: weighing 500mg of arginine powder, calcining for 3h at 240 ℃, naturally cooling to room temperature, dissolving the calcined arginine powder in ultrapure water, performing ultrasonic treatment for 30min, centrifuging for 30min at 15000rpm, adding the supernatant into a dialysis bag with MWCO of 1000Da, dialyzing for 24h in the ultrapure water, and finally performing freeze drying to obtain Arg-CQD nanoparticles; the TEM photograph of the Arg-CQD nanoparticles is shown in FIG. 1, and the result shows that Arg-CQD is round nanoparticles with uniform particle size, and the particle size is about 6 nm.
S12: weighing 1.5g of HA, dissolving in 150mL of deionized water, adding 802mg of potassium permanganate, stirring at room temperature for 2h, adding 200 mu L of glycol to terminate the reaction, adding the reaction solution into a dialysis bag with MWCO being 8000Da, dialyzing in the deionized water for 72h, and finally freeze-drying to obtain HA-CHO; the infrared spectrum of the HA-CHO is shown in FIG. 2, and the result shows that the wavelength is 1731cm -1 A clear-CHO absorption peak is observed, which indicates that HA-CHO is successfully prepared.
S13: 1g GelMA and 50mg LAP (lithium dihydrogen-2, 4,6-trimethyl-benzoyl phosphate, lithium phenyl (2,4, 6-trimethylbenzoyl) phosphate) were weighed out and dissolved in 20mL deionized water, and the solution was dissolved completely at 37 ℃ to obtain a GelMA solution with a concentration of 5% w/v.
S14: and weighing 5mg of Arg-CQD nano-particles prepared in the step S11 and 100mg of HA-CHO prepared in the step S12, adding the Arg-CQD nano-particles and the HA-CHO into 1mL of 5% w/vGelMA solution, placing the solution at 37 ℃ for complete dissolution, and carrying out photo-crosslinking for 30S by using a light source with the wavelength of 405nm to prepare the CQD/HA/GelMA composite hydrogel.
In specific application, the concentration of the Arg-CQD nano-particle is preferably 5 mg/mL; when the content of the Arg-CQD nano particles in the composite hydrogel is gradually increased, the mechanical strength of the composite hydrogel is not obviously changed, but the sterilization performance of the composite hydrogel is gradually enhanced.
Example 2
The preparation method of the CQD/HA/GelMA composite hydrogel of the embodiment comprises the following steps:
s21, weighing 500mg of arginine powder, calcining the arginine powder at 240 ℃ for 3h, naturally cooling the arginine powder to room temperature, dissolving the calcined arginine powder in ultrapure water, performing ultrasonic treatment for 30min, centrifuging the solution at 15000rpm for 30min, adding the supernatant into a dialysis bag with MWCO of 1000Da, dialyzing the solution in the ultrapure water for 24h, and finally performing freeze drying to obtain Arg-CQD nanoparticles;
s22, weighing 1.5g of HA, dissolving in 150mL of deionized water, adding 802mg of potassium permanganate, stirring at room temperature for 2h, adding 200 mu L of ethylene glycol to terminate the reaction, adding the reaction solution into a dialysis bag with MWCO of 8000Da, dialyzing in deionized water for 72h, and finally freeze-drying to obtain HA-CHO;
s23, weighing 1g GelMA and 50mg LAP (lithium dihydrogen-2, 4,6-trimethyl-benzoyl phosphate, phenyl (2,4, 6-trimethylbenzoyl) lithium phosphate) to be dissolved in 20mL deionized water, and placing the solution at 37 ℃ to be completely dissolved to obtain a GelMA solution with the concentration of 5% w/v;
s24, weighing 5mg of Arg-CQD nanoparticles prepared in the step S21 and 200mg of HA-CHO prepared in the step S22, adding the Arg-CQD nanoparticles and the HA-CHO into 1mL of 5% w/vGelMA solution, placing the solution in a condition of 37 ℃ for complete dissolution, and performing photo-crosslinking for 30S by using a light source with the wavelength of 405nm to prepare CQD/HA/GelMA composite hydrogel; the SEM images of the CQD/HA/GelMA composite hydrogel under neutral and acidic conditions are shown in figure 3, and the results show that when the HA-CHO concentration is 10% w/v, compared with a neutral microenvironment, the CQD/HA/GelMA composite hydrogel can be partially degraded under the acidic condition, the macroporous structure is destroyed, the mechanical strength of the composite hydrogel is reduced, and the composite hydrogel can show excellent bactericidal performance. The compression strength diagrams of GelMA, HA/GelMA (hydrogel prepared by photo-crosslinking of a mixed solution of HA-CHO and GelMA and containing no Arg-CQD nanoparticles) and CQD/HA/GelMA composite hydrogel under neutral and acidic conditions are shown in FIG. 4, and the results show that compared with the neutral condition (PBS), the mechanical strength of the HA/GelMA and CQD/HA/GelMA composite hydrogel can be reduced under the acidic condition, which shows that the HA/GelMA and CQD/HA/GelMA composite hydrogel can respond to partial degradation of an acidic microenvironment and damage the structure, so that the mechanical strength of the composite hydrogel is reduced.
Example 3
The preparation method of the CQD/HA/GelMA composite hydrogel of the embodiment includes the following steps:
s31, weighing 500mg of arginine powder, calcining the arginine powder at 240 ℃ for 3h, naturally cooling the arginine powder to room temperature, dissolving the calcined arginine powder in ultrapure water, performing ultrasonic treatment for 30min, centrifuging the solution at 15000rpm for 30min, adding the supernatant into a dialysis bag with MWCO of 1000Da, dialyzing the solution in the ultrapure water for 24h, and finally performing freeze drying to obtain Arg-CQD nanoparticles;
s32, weighing 1.5g of HA, dissolving in 150mL of deionized water, adding 802mg of potassium permanganate, stirring at room temperature for 2h, adding 200 mu L of ethylene glycol to terminate the reaction, adding the reaction solution into a dialysis bag with MWCO of 8000Da, dialyzing in deionized water for 72h, and finally freeze-drying to obtain HA-CHO;
s33, weighing 1g GelMA and 50mg LAP (lithium dihydrogen-2, 4,6-trimethyl-benzoyl phosphate, phenyl (2,4, 6-trimethylbenzoyl) lithium phosphate) to be dissolved in 10mL deionized water, and placing the solution at 37 ℃ to be completely dissolved to obtain a GelMA solution with the concentration of 10% w/v;
s34, weighing 5mg of Arg-CQD nanoparticles prepared in the step S31 and 200mg of HA-CHO prepared in the step S32, adding the Arg-CQD nanoparticles and the HA-CHO into 1mL of 10% w/vGelMA solution, placing the solution in a condition of 37 ℃ for complete dissolution, and performing photo-crosslinking for 30S by using a light source with the wavelength of 405nm to prepare CQD/HA/GelMA composite hydrogel; the release curve diagram of the Arg-CQD nanoparticles of the CQD/HA/GelMA composite hydrogel under neutral and acidic conditions is shown in figure 5, and the result shows that the CQD/HA/GelMA composite hydrogel can respond to an acidic microenvironment to rapidly release the Arg-CQD nanoparticles. Meanwhile, the released Arg-CQD nanoparticles can obviously kill bacteria (figure 6), have good osteogenesis inducing activity and promote cells to generate a large amount of calcium deposition (figure 7).
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 (10)
1. An antibacterial and bone repair promoting hydrogel based on carbon quantum dots is characterized by comprising the following components: arginine carbon quantum dots, oxidized hyaluronic acid and methacryloylated gelatin.
2. The carbon quantum dot-based antibacterial and bone repair promotion hydrogel according to claim 1, wherein the concentration of the arginine carbon quantum dots is 2-20 mg/mL.
3. The carbon quantum dot-based antibacterial and bone repair promoting hydrogel according to claim 1, wherein the concentration of the oxidized hyaluronic acid is 10-30% (w/v).
4. A preparation method of carbon quantum dot-based antibacterial and bone repair promotion hydrogel is characterized by comprising the following steps: adding arginine carbon quantum dots and oxidized hyaluronic acid into a methacrylated gelatin solution, dissolving, and then carrying out a photo-crosslinking reaction to prepare the carbon quantum dot-based antibacterial and bone repair promotion hydrogel.
5. The preparation method of claim 4, wherein the arginine carbon quantum dots are prepared by the following steps: and calcining and cooling arginine powder, dissolving in a solvent, centrifuging, and freeze-drying the centrifuged supernatant to obtain the arginine carbon quantum dot.
6. The preparation method according to claim 5, wherein the calcination temperature is 200-400 ℃, and the calcination time is 3-6 h.
7. The method according to claim 4, wherein the oxidized hyaluronic acid is prepared by: adding a strong oxidant into the HA aqueous solution, uniformly mixing, then adding ethylene glycol to terminate the reaction, and freeze-drying the reaction solution to obtain the oxidized hyaluronic acid.
8. The preparation method according to claim 7, wherein the mass ratio of the HA to the strong oxidant in the HA aqueous solution is 1: 1-5: 1.
9. The method according to claim 7, wherein the strong oxidizing agent is selected from sodium periodate and potassium permanganate.
10. Use of the carbon quantum dot-based antibacterial and bone repair promoting hydrogel according to any one of claims 1 to 3 for the preparation of an infectious bone injury repair medicament.
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