CN117599239A - Dual-slow-release wound healing-promoting and anti-scar dressing and preparation method thereof - Google Patents
Dual-slow-release wound healing-promoting and anti-scar dressing and preparation method thereof Download PDFInfo
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- CN117599239A CN117599239A CN202311626282.1A CN202311626282A CN117599239A CN 117599239 A CN117599239 A CN 117599239A CN 202311626282 A CN202311626282 A CN 202311626282A CN 117599239 A CN117599239 A CN 117599239A
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- dressing
- scar
- parts
- wound healing
- tannic acid
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Classifications
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- A—HUMAN NECESSITIES
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Abstract
The invention relates to a dual slow-release wound healing promoting and anti-scar dressing and a preparation method thereof. Each 100 parts of dressing comprises 5-30 parts of agarose and polyvinyl alcohol double-network hydrogel, 0.1-2 parts of hyperbranched polylysine, 0.1-3 parts of tannic acid, 0.5-10 parts of humectant and the balance of water. The dressing has the advantages of enhanced mechanical property through a double-network structure, swelling resistance, simple preparation and convenient expansion production; and the dressing can realize double slow release of hyperbranched polylysine and tannic acid in the process of promoting wound healing, thereby regulating and controlling the micro-environment of the scar: reducing myofibroblast aggregation, inhibiting the expression of proinflammatory factors, transforming growth factors-beta 1, transforming growth factors-beta 2, alpha-smooth muscle actin and type I collagen, promoting the expression of proinflammatory factors, transforming growth factors-beta 3, type III collagen, etc. The dressing provided by the invention realizes excellent anti-scar effect and can be protected for a long time. The preparation method is high in repeatability, and the obtained dressing is good in mechanical property, has swelling resistance and huge in commercialization potential.
Description
Technical Field
The invention relates to the technical field of biomedical high polymer materials, in particular to a dual slow-release wound healing promoting and anti-scar dressing and a preparation method thereof.
Background
The skin is an organ in direct contact with the outside and is very vulnerable to injury. And scars often occur after the skin has been subjected to deep injuries such as burns, wounds, or surgery. The physical and psychological inconvenience of the life of the patient is caused by the discomfort such as itching, pain and the like and the appearance problems such as swelling, flushing and the like caused by the scar. The formation and development of scars is closely related to the process of wound healing, which typically involves four phases: hemostasis, inflammation, proliferation and remodeling. When problems occur in these phases, such as prolonged inflammatory phases, scarring can easily occur. Therefore, it is necessary to take targeted measures in advance to prevent scar formation and development during wound healing.
In essence, scarring is an inflammatory disease of the reticular dermis, many factors which may promote inflammation leading to scarring, such as oxidative stress. Oxidative stress refers to a pathological condition in which the production of active oxygen in the body is excessive and/or the antioxidant capacity is reduced, the oxidation and antioxidant states are unbalanced and favor oxidation, and the active oxygen and related metabolic wastes are accumulated in a large amount, so that various toxic effects are generated on tissues. Related studies indicate that oxidative stress promotes the formation of pathological scars, and thus antioxidant plays an important role in the control of scars. Another typical factor is bacterial infection, which if not properly treated, wounds can become readily colonized by pathogens, and the emergence of drug resistant bacteria presents further challenges. At present, bacterial infection is mainly treated by applying antibiotics such as tetracyclines, neomycin and quinolones clinically, but due to the induction of bacterial drug resistance, the safety problem under large dosage and the slow development of novel antibiotics in recent years, a non-antibiotic means is urgently required to be searched for antibacterial treatment. In addition, wound healing and subsequent scarring are a process that requires continued attention, short-term burst of functional substances is not desirable, and long-term controlled release is beneficial for dynamic protection of the wound.
The main characteristics of the scar microenvironment are as follows: prolonged inflammatory response, deregulation of transforming growth factor-beta expression, excessive myofibroblast aggregation and extracellular matrix accumulation, and the like. Various inflammatory factors can respond to the inflammatory level, and easily develop into high inflammatory level in scar wounds, high expression of pro-inflammatory factors and low expression of anti-inflammatory factors. Transforming growth factor-beta and its 3 subtypes are highly correlated with the scarring process. Transforming growth factors- β1 and 2 can lead to scarring in which expression is up-regulated; and transforming growth factor-beta 3 can prevent scar, and the expression is down-regulated in scar. Fibroblasts can differentiate into myofibroblasts under the induction of transforming growth factor- β1 or 2. These cells express α -smooth muscle actin, responsible for depositing dense, fibrotic collagen matrix and play a major role in wound contraction, often in scar tissue mass. The major component of the extracellular matrix is collagen, which is predominantly type I and type III in the skin. Coarse type I collagen is the main body, has hard texture, has high content in scars, and makes skin stiff; finer type III collagen can make skin fine and elastic, and has low content in scar.
The existing scar treatment means comprise drug treatment, compression treatment, cryotherapy, operation treatment and the like, and a plurality of scar-removing ointments are also on the market. The above measures all achieve a certain anti-scar effect, but have some defects, such as the need of developing after wound healing, and the inability to realize early intervention on scar formation; not simultaneously giving consideration to antioxidation and antibiosis; the dressing has poor mechanical properties or is not resistant to swelling; the controllable release and long-acting treatment of the functional substances cannot be realized; regulation of scar microenvironment is not a concern.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a dual slow-release wound healing promoting and anti-scar dressing and a preparation method thereof. The dressing has the advantages of enhanced mechanical property through a double-network structure, swelling resistance, simple preparation and convenient expansion production; and the dressing can realize double slow release of hyperbranched polylysine and tannic acid in the process of promoting wound healing, thereby regulating and controlling the micro-environment of the scar and inhibiting the growth of the scar.
The invention solves the technical problems by the following technical proposal:
a dual slow-release wound healing promoting and anti-scar dressing, which comprises the following components in each 100 parts by weight: 5-30 parts of double-network hydrogel formed by agarose and polyvinyl alcohol, 0.1-2 parts of hyperbranched polylysine, 0.1-3 parts of tannic acid, 0.5-10 parts of humectant and the balance of water, and the dressing can simultaneously realize the slow release of the hyperbranched polylysine and the tannic acid.
In the technical scheme, further, the molar ratio of the hyperbranched polylysine to the tannic acid is 1 (0.5-10).
Further, the molar ratio of agarose to polyvinyl alcohol in the double-network hydrogel is 1 (0.1-10).
Further, the humectant is at least one of glycerol, propylene glycol, urea, sodium lactate, trehalose, beta-glucan, sorbitol, olive oil, cholesterol, xylitol, silk peptide and chitin.
The preparation method of the dressing comprises the following steps: dissolving the double-network hydrogel, hyperbranched polylysine and humectant in water at 60-100deg.C; cooling to below 60deg.C, adding tannic acid to combine tannic acid with hyperbranched polylysine; adjusting pH to 6.0-8.3, forming gel, packaging, and sterilizing.
The dressing has excellent mechanical properties, and can hyperbranched polylysine and tannic acid serving as dual slow-release functional substances in the process of promoting healing of infected wound surfaces, the micro-environment of the scar is regulated, and the regulation of the micro-environment of the scar is shown in the following steps:
reducing myofibroblast aggregation, inhibiting the expression of pro-inflammatory factors, transforming growth factors-beta 1, transforming growth factors-beta 2, alpha-smooth muscle actin and type I collagen, and promoting the expression of anti-inflammatory factors, transforming growth factors-beta 3 and type III collagen; can effectively promote healing and resist scar.
Compared with the prior art, the invention has the following beneficial effects:
1. the antibacterial dressing provided by the invention can promote healing of infected wounds and inhibit subsequent scar formation, and further can regulate and control scar microenvironments such as inflammatory factors, transforming growth factors-beta, myofibroblasts, alpha-smooth muscle actin, collagen types and the like.
2. The antibacterial dressing provided by the invention adopts the combined action of hyperbranched polylysine and tannic acid, and realizes slow release through the electrostatic combination of the hyperbranched polylysine and tannic acid and the hydrogen bond action with the double-network hydrogel, thereby achieving the long-term protection of infected wounds and the continuous regulation and control of scar microenvironment.
3. The preparation method provided by the invention does not involve complex chemical synthesis, has high safety and small resistance to productization, and the obtained hydrogel dressing has strong mechanical property and can resist swelling, thereby ensuring effective application on multi-liquid-seepage wounds.
Drawings
FIG. 1 is a tensile stress-strain curve of the hydrogel dressing PAHT of example 1 and PAHT after swelling equilibrium;
FIG. 2 is a graph showing the release profile of hyperbranched polylysine (hyperbranched polylysine, HBPL) in PAH and PAHT and (B) Tannic Acid (TA) in PAT and PAHT of the hydrogel dressing of example 1;
FIG. 3 shows the scavenging efficiency of hydrogel dressing of example 1 on (A) DPPH radical, (B) hydroxyl radical, (C) superoxide anion and (D) hydrogen peroxide;
FIG. 4 shows (A) cell compatibility and (B) blood compatibility of the hydrogel dressing of example 1;
FIG. 5 is a photograph of a wound surface of a hydrogel dressing of example 1 applied to a wound model of an infected rat at various time points;
FIG. 6 shows the amounts of expression of (A) tumor necrosis factor-alpha (tumor necrosis factor-alpha, TNF-alpha), (B) interleukin-1 beta (interleukin-1 beta, IL-1 beta), (C) interleukin-6 (interleukin-6, IL-6), (D) interleukin-4 (interleukin-4, IL-4) and (E) interleukin-10 (interleukin-10, IL-10) in wound tissue on day 3 of application of the hydrogel dressing of example 1 to infected rat wound models;
FIG. 7 shows bacterial (A) colony culture and (B) quantitative statistics in wound tissue at day 6 of application of the hydrogel dressing of example 1 to infected rat wound models;
FIG. 8 shows the H & E staining of wound tissue, masson staining, sirius red staining and alpha-smooth muscle actin (alpha-smooth muscle actin antibody, alpha-SMA) immunofluorescence staining of polarized light of example 1 applied to day 56 wound tissue in infected rabbit ear scar model;
FIG. 9 shows (A) differential gene thermogram and (B) KEGG pathway analysis obtained after transcriptome analysis of wound tissue on day 56 of the three Norm, ctrl and PAHT groups in the rabbit ear scar model of the hydrogel dressing of example 1.
Detailed Description
The following examples further illustrate the technical aspects of the present invention, but are not intended to limit the present invention.
Example 1:
synthesis of hydrogel dressing:
first, 20wt% of polyvinyl alcohol 1799 and 2wt% of agarose are dissolved in 76.2wt% of water under mechanical stirring and heating at 110 ℃; then cooling to 90 ℃, adding 1wt% of hyperbranched polylysine, adding 0.8wt% of tannic acid after 30 minutes, and adjusting the pH to 6 by using 1.2M hydrochloric acid; after complete dissolution, the solution was poured into a mold and cooled to room temperature, then put into a-20 ℃ refrigerator for 4h, thawed at room temperature for 1h, and circulated for 3 times. The resulting hydrogel was designated PAHT, and other comparative hydrogels used in this example were also prepared by this method, with abbreviations and compositions for the different hydrogels shown in Table 1.
TABLE 1 abbreviations and Components of different hydrogels
1) The mechanical properties of the hydrogels were tested by tensile experiments on a universal material tester. FIG. 1 shows that the tensile elastic modulus, elongation at break and strength at break of PAHT hydrogels are around 100kPa, 450% and 0.9MPa, respectively, which are also famous for similar hydrogel dressing products, and mainly benefit from the dual network structure composed of polyvinyl alcohol and agarose. And the PAHT hydrogel has a swelling resistance function, and has a breaking strength of 0.57MPa and an elongation at break of 330% after swelling balance, which indicates that the PAHT hydrogel can completely overcome the application occasion with a large number of exudates wound.
2) The release of hyperbranched polylysine from the hydrogel was determined by fluorescent labeling and the release of tannic acid was determined by colorimetry. The release rate was faster for either hyperbranched polylysine (FIG. 2A) or tannic acid (FIG. 2B) alone than for both. It can be seen that hyperbranched polylysine and tannic acid are simultaneously added into the double-network hydrogel, and the slow release of the hyperbranched polylysine and tannic acid and the hydrogen bond interaction with the hydrogel main body are simultaneously realized through the electrostatic interaction of the hyperbranched polylysine and the tannic acid, so that the hyperbranched polylysine and the tannic acid can continuously act on a wound environment.
3) The antioxidant capacity of the hydrogel was tested by testing the hydrogel against DPPH, OH and O 2 - And H 2 O 2 Is characterized by its ability to clear. As shown in fig. 3A-D, both PAT and PAHT hydrogels containing tannic acid showed good scavenging effect, while the hydrogel matrix and hyperbranched polylysine provided some auxiliary antioxidant effect. Overall, the hydrogel PAHT exhibits excellent antioxidant capacity.
4) Toxicity of hydrogels to L929 cells was tested by CCK-8 experiments, and after 1 day of incubation, all groups maintained more than 90% of the cellular activity compared to the control group (FIG. 4A). Anticoagulated sheep blood was used to test the haemolysis of the hydrogels, with haemolysis rates below 1% for all hydrogel groups (fig. 4B). These results demonstrate that hydrogels have good cellular and blood compatibility and can be further studied in vivo.
5) A full-thickness skin defect model of rats resistant to methicillin-resistant staphylococcus aureus infection was constructed to evaluate the ability of each hydrogel to promote healing of infected wounds, with no measures applied by the Ctrl group. As shown in fig. 5, the healing of PAHT group with simultaneous addition of hyperbranched polylysine and tannic acid was always best in 12 days, and the final wound surface was almost completely closed, demonstrating that PAHT hydrogel can significantly promote healing of infected wound.
6) In the full-thickness skin defect model of infected rats, wound tissues were taken on day 3 to test the content of each inflammatory factor. As shown in fig. 6A-C, three pro-inflammatory factors, tumor necrosis factor- α, interleukin-1 β and interleukin-6, were expressed lowest in the PAHT group, and correspondingly, anti-inflammatory factors interleukin-4 and interleukin-10 were expressed highest (fig. 6D, E), indicating that PAHT hydrogels were effective in reducing inflammation.
7) In the full-thickness skin defect model of infected rats, wound tissue was taken on day 6 to test residual bacterial content. As shown in FIG. 7A, the PAH and PAHT group containing hyperbranched polylysine had the lowest bacterial content, as also demonstrated by the quantitative statistics in FIG. 7B. Hyperbranched polylysine is used as a novel mild and efficient antibacterial agent, and the bacterial cell membrane is destroyed mainly by a large number of positively charged amino groups to achieve the sterilization effect, so that the drug resistance is not caused, the safety problem is avoided, and the novel antibacterial agent is a new star which is raised in the late antibiotic era. After the hyperbranched polylysine is loaded, the PAHT hydrogel can strongly treat the infected wound surface and protect the wound surface from being affected by bacteria.
8) The ability of each hydrogel to inhibit the hypertrophic scar and regulate the scar microenvironment was assessed by a methicillin-resistant staphylococcus aureus infection rabbit ear hypertrophic scar model, and likewise, ctrl group did not apply any measures for a total of 4 weeks, followed by a further 4 week treatment to stabilize the scar. As shown in FIG. 8, on the one hand, H & E staining can visually indicate scar thickness, and the Ctrl group without hydrogel treatment produced scars with an average thickness of 936.0 μm, more than twice the normal skin thickness (357.2 μm). With increasing hydrogel function (pa→pat→pah→paht), scar thickness gradually decreased, with average scar thickness for the PAHT group being 592.5 μm, a 36.7% decrease compared to Ctrl group. On the other hand, the untreated Ctrl group showed a maximum of 63.1% while the PAHT group (45.4%) was closest to the normal level (38.7%) as observed by Masson staining, demonstrating that excessive deposition of collagen was inhibited. In addition, by observing sirius red staining with polarized light, type I (orange) and type III (green) collagens can be distinguished, and the type III collagen hardly exists in Ctrl group, and the proportion of type III collagen is obviously increased after the treatment of functional hydrogel. Finally, the content of the marker of the conversion of the fibroblast, alpha-smooth muscle actin, to myofibroblast in the different groups was observed by immunofluorescence staining, and the expression in Ctrl group was particularly evident, and the expression of alpha-smooth muscle actin gradually decreased with increasing hydrogel function, and the PAHT group was already near normal skin level. In conclusion, the antibacterial and antioxidant hydrogel dressing PAHT has remarkable inhibition effect on the generation of hypertrophic scars, and can further regulate and control the scar microenvironment.
9) In the infected rabbit ear hypertrophic scar model, transcriptome analysis was used to explore the intrinsic mechanism of PAHT hydrogel scar inhibition. As shown in FIG. 9A, the gene heatmap shows that genes associated with immune responses and inflammatory responses are significantly up-regulated in the Ctrl group compared to the Nor group, and that expression of these genes returns to near Nor group levels after PAHT treatment. Genes up-regulated in Ctrl vs Norm and down-regulated in PAHT vs Ctrl were collected and potential signaling pathways were analyzed by kyoto gene and encyclopedia of genome (KEGG). As shown in fig. 9B, the results indicate that the differential genes are significantly involved in pathways related to host defense, immunomodulation, inflammatory pathways, and the like. Overall, PAHT hydrogels achieve effects of promoting tissue healing and reducing scarring by treating infections and controlling inflammation.
The above embodiments are only for illustrating the technical solution of the present invention, and those skilled in the art may make many changes or additions to the form and detail thereof, which changes and additions should also be construed as being within the scope of the present invention, based on the contents of the present invention and the parts of the specific embodiments.
Claims (6)
1. A dual slow-release wound healing promotion and anti-scar dressing, which is characterized by comprising the following components in each 100 parts by weight: 5-30 parts of double-network hydrogel formed by agarose and polyvinyl alcohol, 0.1-2 parts of hyperbranched polylysine, 0.1-3 parts of tannic acid, 0.5-10 parts of humectant and the balance of water, and the dressing can simultaneously realize the slow release of the hyperbranched polylysine and the tannic acid.
2. The dual slow-release wound healing and anti-scar dressing of claim 1, wherein the molar ratio of hyperbranched polylysine to tannic acid is 1 (0.5-10).
3. The dual slow-release wound healing and anti-scar dressing of claim 1, wherein the molar ratio of agarose to polyvinyl alcohol in the dual-network hydrogel is 1 (0.1-10).
4. The dual slow release wound healing and anti-scarring dressing according to claim 1, wherein the humectant is at least one of glycerin, propylene glycol, urea, sodium lactate, trehalose, β -glucan, sorbitol, olive oil, cholesterol, xylitol, silk peptide, and chitin.
5. A method for preparing a dual slow release wound healing promoting and anti-scarring dressing according to any one of claims 1 to 4, comprising the steps of: dissolving the double-network hydrogel, hyperbranched polylysine and humectant in water at 60-100deg.C; cooling to below 60deg.C, adding tannic acid to combine tannic acid with hyperbranched polylysine; adjusting pH to 6.0-8.3, forming gel, packaging, and sterilizing.
6. The method for preparing the dual slow-release wound healing promotion and anti-scar dressing according to claim 5, wherein the gelling method comprises the following steps: freezing the hydrogel precursor solution at-20 to-80deg.C for 4 to 24 hours, thawing at room temperature to 60deg.C for 1-12 hr, and circulating for 2-3 times.
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