An antibacterial and wound-healing promoting hydrogel composite dressing and its preparation method
By grafting polypolyol acrylate on POSS molecules and loading antibacterial nanoparticles, the modified POSS material mixed with bacterial cellulose to form an antibacterial healing hydrogel dressing, the problem of insufficient antibacterial performance and strength of existing hydrogels is solved, and better wound healing effect is achieved.
Patent Information
- Application Number
- CN202411150398.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-21
- Publication Date
- 2025-07-25
- Estimated Expiration
- 2044-08-21
AI Technical Summary
The existing bacterial cellulose hydrogel dressings have shortcomings in antibacterial properties, strength and healing ability, and cannot effectively prevent wound infection and accelerate healing, especially in skin wounds caused by diabetes.
By grafting the polypolyol acrylate monomer on the POSS molecules and loading antibacterial nanoparticles, a modified POSS material is formed mixed with bacterial cellulose to form an antibacterial pro-healing hydrogel composite dressing, which enhances mechanical properties and biocompatibility of the polypolyol to promote healing.
It significantly improves the antibacterial properties and mechanical strength of the hydrogel, provides a moist healing environment, promotes cell growth, reduces scar formation, relieves pain, and accelerates wound recovery.
Smart Images
Figure CN119345445B_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of medical materials, and particularly relates to an antibacterial and wound-healing promoting hydrogel composite dressing and a preparation method thereof. Background Art
[0002] Skin wounds caused by diabetes are due to persistent hyperglycemia levels and related diabetic complications. Diabetic skin wounds have an extremely complex pathology, and the delay in wound healing involves multiple pathophysiological mechanisms, including overactivation of the tissue area immune response, oxidative stress, reduction of new blood vessels, peripheral neuropathy, extracellular matrix accumulation, and imbalance in remodeling, etc. At the molecular level, epigenetic modifications, activation of pattern recognition receptors, mitochondrial dysfunction, and abnormal energy metabolism are all related to the delay in diabetic skin wound healing.
[0003] Traditional dressings, such as gauze, sterilized absorbent cotton, bandages, etc., are the most widely used clinical dressings due to their low cost and simple manufacturing process; applying them on the surface of skin wounds caused by diabetes can promote wound healing. Although traditional dressings can protect the wound from external infections, they lack controllable wound absorbency and are too dry, resulting in the inability of the wound to heal in a timely manner. In addition, in the case of excessive wound drainage, they may adhere to the wound, making it difficult to remove the dressing. Therefore, traditional dressings are usually used for mildly squeezed wounds or as auxiliary dressings.
[0004] Hydrocolloid dressings are medical dressings composed of hydrocolloid molecules with strong water absorption capacity, a glue matrix with adhesive properties, and a semi-permeable protective film. Compared with traditional dressings, hydrogel dressings can keep the wound moist, have better biocompatibility and degradability; they can be replaced or removed without severely damaging the wound tissue, which is their greatest advantage. In addition, hydrogel dressings are flexible, can adhere to the wound, will not cause extrusion to the wound, and can absorb exudate, permeate oxygen and metabolites, and prevent bacteria from entering. However, generally, traditional gels themselves do not have antibacterial activity to prevent bacterial infection of the wound, and hydrogels themselves cannot achieve the effect of promoting wound healing. In addition, traditional hydrogels also have the disadvantages of low strength and poor toughness.
[0005] Bacterial cellulose is a cellulose hydrogel synthesized by bacteria with good biocompatibility. It has a three-dimensional network structure composed of nanofibers, with micron-sized pores, a high porosity, and a large specific surface area. Therefore, it has good air permeability and can effectively block the invasion of bacteria. Compared with traditional hydrogels, bacterial cellulose-based hydrogels have a high water content, an appropriate porosity, and good cell compatibility. They can provide the required wettability for the wound surface, and can also carry out gas exchange and absorb exudates. The bacterial cellulose-based hydrogel can be easily trimmed into any shape, making it easy to fully contact the wound site, convenient for wrapping and filling the wound, thereby improving the self-healing effect. In addition, a large number of carboxyl groups are contained in the cellulose molecular structure, which can combine with iron ions in hemoglobin in the blood, and then activate coagulation factors to promote blood coagulation. At the same time, it can promote the adhesion of platelets in the blood and enhance the hemostatic effect. However, usually a single cellulose-based hydrogel also has the disadvantages of traditional hydrogels, that is, it has no antibacterial activity to prevent wound infection, and the bacterial cellulose hydrogel itself cannot achieve the effect of promoting wound healing. In addition, the bacterial cellulose hydrogel also has the disadvantages of low strength and poor toughness. At present, aiming at the disadvantages of insufficient antibacterial performance, inability to promote wound healing, low strength, and poor toughness of cellulose hydrogels, many researchers have tried to solve them by adding antibacterial agents, specific functional materials, etc. However, for the current modification methods of bacterial cellulose hydrogels, the functions achieved are relatively single, and the functions of providing antibacterial, improving the strength of the hydrogel, and promoting wound healing cannot be achieved simultaneously. Therefore, it is urgently necessary to develop a multi-functional nanomaterial to improve the various properties of cellulose hydrogels. Summary of the Invention
[0006] The purpose of the present invention is to solve the deficiencies of the prior art, and further provide an antibacterial and wound-healing hydrogel composite dressing, which is obtained by mixing bacterial cellulose and a modified POSS material; the above-mentioned modified POSS material is obtained by grafting monomers onto reactive groups in POSS molecules and then loading antibacterial nanoparticles on the surface; the above-mentioned monomer is polyol acrylate; the above-mentioned reactive groups are selected from vinyl, acryloyloxy, or acrylic acid groups.
[0007] In the present invention, polyol acrylate is grafted onto POSS molecules (i.e., cage-shaped polyhedral oligomeric silsesquioxane). On the one hand, it can endow the modified POSS material with good water solubility and dispersibility in the hydrogel, reducing the agglomeration phenomenon. On the other hand, the terminal hydroxyl groups and ether bonds in the grafted polyol molecular chain can interact with the polar groups such as the side hydroxyl groups and carboxyl groups of bacterial cellulose to form hydrogen bonds, and the rigid cage structure of POSS also has good modulus and strength. The two cooperate with each other to jointly enhance the mechanical properties of the cellulose-based hydrogel. In addition, the grafted polyol molecular chain has good biocompatibility like the POSS molecule, and also has good wetting and moisturizing properties, which can provide a moist microenvironment conducive to cell growth for diabetic wound surfaces, thereby promoting the wound healing process, reducing scar formation, and effectively alleviating the pain of patients. It also has excellent oxygen permeability and antibacterial ability, which can effectively prevent wound infection and further accelerate the wound recovery process. Moreover, due to the good water solubility and dispersibility of the POSS molecule grafted with polyol, it can be more uniformly dispersed in the aqueous solution, which is more conducive to the process of loading antibacterial nanoparticles, thereby endowing the modified POSS material of the present invention with antibacterial efficacy.
[0008] The structural formula of the POSS molecule is shown as follows:
[0009]
[0010] Among them, R can be independently selected from different groups, including reactive groups and inert groups. In the invention, at least 1 R needs to be a reactive group, that is, at least 1 reactive group exists in the POSS molecule used in the present invention to achieve the above effects.
[0011] After research, the reactive group can only be selected from vinyl, acryloyloxy or acrylic acid groups. Only these groups can polymerize under ultraviolet light irradiation to achieve the subsequent grafting reaction. In addition, pure polyol cannot directly achieve polymerization grafting under ultraviolet light irradiation. Therefore, polyol with acrylate groups must also be used to cooperate with the specially selected reactive groups to achieve polymerization grafting under ultraviolet light conditions and graft the polyol molecular chain onto POSS.
[0012] In some preferred embodiments, the above monomer is at least one of polyethylene glycol diacrylate, polypropylene glycol diacrylate, polyethylene glycol monomethyl ether acrylate, polyethylene glycol dimethacrylate and polybutylene glycol diacrylate.
[0013] In some preferred embodiments, the number of the above reactive groups is 8. The POSS molecules are hybridized into the hydrogel as crosslinking points. When there are more reactive groups in the POSS molecules, multiple reactive groups can all undergo chemical crosslinking. Compared with fewer reactive groups, there are more crosslinking points, so the crosslinking density is greater at the same content, and the enhancement effect on mechanical strength is better.
[0014] In some preferred embodiments, the above antibacterial nanoparticles are at least one of silver nanoparticles, titanium dioxide nanoparticles, zinc oxide nanoparticles, and copper oxide nanoparticles.
[0015] In some preferred embodiments, the above modified POSS material accounts for 10%-40% of the mass of the above bacterial cellulose. If the proportion of the modified POSS material is too high, the proportion of bacterial cellulose will be too low, which will affect the formation of the hydrogel; if the proportion of the modified POSS material is too low, the antibacterial effect, hydrogel strength, and wound healing promotion effect will be affected to a certain extent.
[0016] The present invention also provides a preparation method of the above antibacterial and wound healing promoting hydrogel composite dressing, including the following steps: mixing the above bacterial cellulose and the above modified POSS material to obtain the above antibacterial and wound healing promoting hydrogel composite dressing; wherein, the preparation process of the above modified POSS material is as follows: under the conditions of an ultraviolet light initiator and ultraviolet light irradiation, graft the above monomer onto the reactive groups of the above POSS molecules, and then surface load the above antibacterial nanoparticles through a redox reaction.
[0017] The present invention modifies by ultraviolet light-induced grafting. The modification method steps are simple and convenient. By changing conditions such as irradiation intensity, irradiation time, and monomer concentration, the length of the polyol molecular chain after grafting can be regulated, so as to optimize the performance of the modified POSS material.
[0018] In some cases, the irradiation light source can use a UVLED light source, and the irradiation intensity can be 2000 mW / cm 2 -10000 mW / cm 2 , preferably 5000 mW / cm 2 , and the irradiation time can be 0.5 h - 6 h, preferably 1 h. If the irradiation intensity is too strong or the irradiation time is too long, the molecular chain of the grafted polyol will polymerize too long, which will lead to difficulty in modifying and loading antibacterial nanoparticles on the POSS, and self-polymerization between monomers is also more likely to occur; if the irradiation intensity is too low or the irradiation time is too short, the polymerization reaction of the grafted polyol molecular chain is insufficient, which will also result in too short a molecular chain of the polyol grafted on the POSS, being not conducive to the dispersion of the POSS in the aqueous solution.
[0019] In some embodiments of the above preparation method, the modified POSS material is dispersed in water, and then the bacterial cellulose is added, and the antibacterial and wound-healing hydrogel composite dressing is formed by mixing. Further, after the bacterial cellulose and the modified POSS material are mixed, the obtained hydrogel is subjected to freeze-drying treatment. The modified POSS material is still an inorganic material. Dispersing it in water first can make the grafted polyol molecular chains more fully unfolded, and then be more fully dispersed in water and less likely to agglomerate. If cellulose is added first, it is likely to cause an increase in the viscosity of the solution system. At this time, adding the modified POSS material is not conducive to the full dispersion of the modified POSS material, and it is easy to produce certain agglomeration, resulting in adverse effects such as a decrease in mechanical properties and uneven antibacterial effects.
[0020] In some embodiments of the above preparation method, the ultraviolet light initiator is at least one of polyethylene glycol diacrylate, polypropylene glycol diacrylate, polyethylene glycol monomethyl ether acrylate, polyethylene glycol dimethacrylate, and polybutylene glycol diacrylate; the dosage of the ultraviolet light initiator is 0.5%-5% of the mass of the monomer; the dosage of the monomer is 50%-300% of the mass of the POSS molecule.
[0021] The beneficial effects of the present invention are as follows: The composite dressing of the present invention is safe and non-toxic. Compared with traditional hydrogel dressings, it further improves the antibacterial performance, mechanical strength, and wound-healing ability, can better relieve the pain of patients, and accelerate the recovery process; and the preparation method is simple and controllable, and can be produced and applied on a large scale. BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Figure 1 Shown is the scanning electron microscope image of the vinyl POSS molecule in Example 1;
[0023] Figure 2 Shown is the transmission electron microscope image of the modified POSS material in Example 1;
[0024] Figure 3 Shown is the product image of the antibacterial and wound-healing hydrogel in Example 1;
[0025] Figure 4 Shown is the photo image of the container filled with the antibacterial and wound-healing hydrogel in an inverted state in Example 1;
[0026] Figure 5 Shown is the stress-strain curve graph of the composite dressing;
[0027] Figure 6 Shown is the antibacterial effect graph of the composite dressing;
[0028] Figure 7 Shown is the result graph of the live-dead bacteria staining test of the composite dressing;
[0029] Figure 8 The figure shows the wound healing rate graph of the composite dressing. Detailed implementation manners
[0030] The concept and technical effects of the present invention will be clearly and completely described below in combination with the embodiments and the drawings, so as to fully understand the purpose, solution and effects of the present invention. It should be noted that, without conflict, the embodiments in the present application and the features in the embodiments can be combined with each other.
[0031] In the POSS molecules in the following embodiments, their structures are as shown below:
[0032]
[0033] Example 1
[0034] An antibacterial and wound-healing hydrogel composite dressing, and its preparation method includes the following steps:
[0035] (1) Synthesis of modified POSS material:
[0036] a. Graft modification: Dissolve and disperse 500 mg of vinyl POSS molecules (i.e., all 8 R groups are vinyl; its scanning electron microscope image is as Figure 1 shown, and it can be seen from Figure 1 that most of the pure POSS molecules are in a cubic state) in 20 mL of tetrahydrofuran (THF); it should be noted that in some other implementation manners, chloroform or dichloromethane can be used to replace THF;
[0037] Then, add 400 mg of polyethylene glycol diacrylate (monomer) and 10 mg of 1-hydroxycyclohexyl phenyl ketone (ultraviolet light initiator) to the above solution, and stir evenly; then transfer the solution to the condition of ultraviolet light irradiation, with an irradiation intensity of 3000 mW / cm 2 , irradiate for 3 hours; then wash with THF and DMF in sequence to remove the unreacted monomers, centrifuge, and dry to obtain the grafted POSS sample;
[0038] b. Loading treatment: Add 200 mg of the grafted POSS sample prepared above to 50 mL of silver ammonia solution, ultrasonically disperse for 10 min, then stir vigorously at 60 °C for 1 h (rotation speed is 800 rpm), centrifuge and filter to obtain the modified POSS material loaded with silver nanoparticles; its transmission electron microscope image is as Figure 2 shown, and it can be seen from Figure 2 that the prepared modified POSS material is in a spherical state, has a core-shell structure, and is simultaneously loaded or modified with silver nanoparticles on the surface.
[0039] (2) Synthesis of antibacterial and wound-healing hydrogel composite dressing:
[0040] Take 100 mg of the modified POSS material prepared in the above (1), add it to 20 mL of deionized water, stir evenly, heat and maintain at 50 °C, then add 1 g of bacterial cellulose to the solution, and stir vigorously at 800 rpm for 60 min until the solution becomes clear and transparent to obtain the antibacterial and wound-healing hydrogel, namely cellulose / 10 wt% modified POSS composite dressing; as Figure 3 and Figure 4 shown, from Figure 3 and Figure 4 it can be seen that the prepared hydrogel has a certain viscosity and does not flow even when the container is inverted. Finally, perform freeze treatment, that is, place the above hydrogel at -20 °C for 24 h, and then thaw at room temperature for 4 h; repeat the above freeze treatment 3 times, and then perform freeze-drying to remove moisture to obtain the antibacterial and wound-healing hydrogel composite dressing.
[0041] Example 2
[0042] An antibacterial and wound-healing hydrogel composite dressing, the difference in its preparation method from that of Example 1 lies in: the content of the modified POSS material loaded with silver nanoparticles added is 20 wt% relative to bacterial cellulose; others are the same as in Example 1.
[0043] Example 3
[0044] An antibacterial and wound-healing hydrogel composite dressing, the difference in its preparation method from that of Example 1 lies in: the content of the modified POSS material loaded with silver nanoparticles added is 30 wt% relative to bacterial cellulose; others are the same as in Example 1
[0045] Comparative Example 1
[0046] A composite dressing, the difference in its preparation method from that of Example 1 lies in: there is no grafting modification step and no loading treatment step for loading silver nanoparticles. Directly perform the same steps as in step (2) of Example 1 on the same vinyl POSS molecules in Example 1 (that is, all 8 R groups are vinyl); other processes are the same as in Example 1.
[0047] Effect test
[0048] (1) Mechanical test
[0049] Perform mechanical tests on the antibacterial and wound-healing hydrogel composite dressing (i.e., bacterial cellulose / modified POSS composite dressing) prepared in Example 1, the composite dressing (i.e., bacterial cellulose / POSS composite dressing) prepared in Comparative Example 1, and the pure bacterial cellulose dressing (i.e., blank control group). The results of the stress-strain curves of the tensile tests are as Figure 5As shown by Figure 5 It can be seen that the composite dressing of the present invention has better strength and elongation at break.
[0050] (2) Antibacterial effect test
[0051] The antibacterial and healing-promoting hydrogel composite dressing prepared in Example 1 (i.e., cellulose / 10wt% modified POSS composite dressing), the antibacterial and healing-promoting hydrogel composite dressing prepared in Example 2 (i.e., cellulose / 20wt% modified POSS composite dressing), the antibacterial and healing-promoting hydrogel composite dressing prepared in Example 3 (i.e., cellulose / 30wt% modified POSS composite dressing), the composite dressing prepared in Comparative Example 1 (i.e., cellulose / 10wt% POSS composite dressing), and the pure bacterial cellulose dressing (i.e., pure cellulose dressing) were subjected to antibacterial performance test and live and dead bacteria staining test.
[0052] Antibacterial performance experiment: Take 1×10 6 150 μL of CFU / mL Escherichia coli suspension was added to the test tube, and 150 μL of Luria-Bertani (LB) liquid culture medium (control group) and the above-mentioned dressings were added at the same time. After thorough mixing, the mixture was co-cultured at 37°C and 100 r / min for 48 h. The absorbance of each group at a wavelength of 600 nm was measured with an enzyme marker at 0 h and 48 h to determine the antibacterial performance.
[0053] Live / dead bacterial staining test: 200 μL of each dressing was added to a 24-well plate and allowed to gel in a 37°C sterile incubator. Then 200 μL of 1.0×10 6 CFU / mL of E. coli suspension were co-cultured at 37°C for 24 hours, and the control group was an E. coli suspension containing LB liquid culture medium. After 24 hours, LIVE / DEADBacLight staining solution (Invitrogen, USA) was added to the experimental group and the control group respectively, and incubated in the dark for 15 minutes. The fluorescence images were observed by laser confocal microscopy, and the fluorescence intensity of dead and live bacteria in each treatment group was calculated.
[0054] The results are as follows Figure 6 and Figure 7 As shown by Figure 6 It can be seen that pure POSS molecules and pure bacterial cellulose hydrogels have no antibacterial effect, while the composite dressing prepared in Example 1 has a good antibacterial rate. When its content is greater than or equal to 20wt%, the antibacterial rate can reach nearly 100%.
[0055] (3) Animal testing
[0056] Animal experiments were conducted on the antibacterial and wound-healing hydrogel composite dressing prepared in Example 1 (i.e., bacterial cellulose / modified POSS composite dressing), Comparative Example 1 (i.e., bacterial cellulose / POSS composite dressing), and pure bacterial cellulose dressing (i.e., the control group); specifically: After acclimating the mice for 1 week, they were switched to a high-fat diet (with 60% of the energy supplied by fat) and fed for another 4 weeks. Then, freshly prepared streptozotocin solution (0.01 mL / g) was intraperitoneally injected continuously for 5 days, and the mice were fasted for 12 hours before each injection without restricting water intake; on the 6th and 7th days, the fasting blood glucose levels of the mice were measured by tail vein blood sampling for 2 consecutive days, and the mice with blood glucose levels higher than 11 mmol / L were selected for the experiment. Then, the mice were randomly divided into 3 groups, with 3 mice in each group, namely the control group (PBS solution) and the composite hydrogels of different groups. After anesthetizing the mice intraperitoneally with 1% sodium pentobarbital, the hair on their backs was removed, they were rinsed with warm physiological saline, dried, disinfected with iodine tincture, and a full-thickness skin with a diameter of about 1 cm was cut off on the backs of the mice to prepare a wound model. 100 μL of E. coli (1×10 6 CFU / mL) dissolved in physiological saline was inoculated onto the skin wounds. After 1 day of infection, 200 μL of the solutions of the control group and each experimental group were placed on the back wounds, and the wound healing area and healing time were observed and recorded on the 0th, 3rd, 7th, 10th, and 14th days after the trauma. The wound healing rate was calculated according to the following formula, and the wound healing speed was evaluated. Wound healing rate = (initial wound area - wound area after healing) / initial wound area × 100%.
[0057] The results are as Figure 8 shown, and it can be seen from Figure 8 that after 14 days of treatment, the wound healing effect of the mice using the composite dressing prepared in Example 1 was significantly better than that of the wounds using the composite dressings of Comparative Example 1 and the control group.
[0058] As mentioned above, it is only a preferred embodiment of the present invention. The present invention is not limited to the above-mentioned embodiments. As long as it achieves the technical effects of the present invention by the same means, it should fall within the protection scope of the present invention. Within the protection scope of the present invention, various modifications and changes can be made to its technical solutions and / or implementation manners.
Claims
1. An antibacterial and wound-healing promoting hydrogel composite dressing, characterized in that, The antibacterial and wound-healing hydrogel composite dressing is obtained by mixing bacterial cellulose and a modified POSS material; the modified POSS material is obtained by grafting monomers onto reactive groups in the POSS molecule and then surface-loading antibacterial nanoparticles; the monomer is polyol acrylate; the reactive groups are selected from vinyl, acryloyloxy or acrylic groups; The preparation process of the modified POSS material is as follows: under the conditions of a UV initiator and UV irradiation, graft the monomer onto the reactive groups of the POSS molecule, and then surface-load the antibacterial nanoparticles through a redox reaction.
2. The antibacterial and wound-healing promoting hydrogel composite dressing according to claim 1, wherein The number of the reactive groups is 8.
3. The antibacterial and wound-healing promoting hydrogel composite dressing according to claim 1 or 2, wherein The monomer is at least one of polyethylene glycol diacrylate, polypropylene glycol diacrylate, polyethylene glycol monomethyl ether acrylate, polyethylene glycol dimethacrylate and polybutylene glycol diacrylate.
4. The antibacterial and wound-healing promoting hydrogel composite dressing according to claim 1, wherein The antibacterial nanoparticles are at least one of silver nanoparticles, titanium dioxide nanoparticles, zinc oxide nanoparticles and copper oxide nanoparticles.
5. The antibacterial and wound-healing promoting hydrogel composite dressing according to claim 1, wherein The modified POSS material accounts for 10%-40% of the mass of the bacterial cellulose.
6. A preparation method of the antibacterial and wound-healing promoting hydrogel composite dressing according to any one of claims 1 to 5, characterized in that, It includes the following steps: mix the bacterial cellulose and the modified POSS material to obtain the antibacterial and wound-healing hydrogel composite dressing; The preparation process of the modified POSS material is as follows: under the conditions of a UV initiator and UV irradiation, graft the monomer onto the reactive groups of the POSS molecule, and then surface-load the antibacterial nanoparticles through a redox reaction.
7. The preparation method according to claim 6, characterized in that, Disperse the modified POSS material in water, and then add the bacterial cellulose and mix to form the antibacterial and wound-healing hydrogel composite dressing.
8. The preparation method according to claim 6, characterized in that, The dosage of the UV initiator is 0.5%-5% of the mass of the monomer.
9. The preparation method according to claim 6, characterized in that, The conditions of ultraviolet light irradiation include: the irradiation intensity is 2000 mW / cm 2 - 10000 mW / cm 2 , and the irradiation time is 0.5 h - 6 h.
10. The preparation method according to claim 6, characterized in that, The dosage of the monomer is 50%-300% of the mass of the POSS molecule.