A paper recently published in the journal Biomaterials Advances demonstrated the effectiveness of a novel near-infrared (NIR) photothermal injectable hydrogel with anti-inflammation and anti-oxidation properties in treating skin defects.
Study: Scavenging ROS and inflammation produced during treatment to enhance the wound repair efficacy of photothermal injectable hydrogel. Image Credit: supanee sukanakintr/Shutterstock.com
Injectable hydrogels prepared from natural polymers, such as sodium alginate, gelatin, and chitosan, have gained significant attention for skin defect treatment owing to their excellent biodegradability and biocompatibility. Additionally, they are suitable for treating irregular wound defects.
However, these natural polymer-based injectable hydrogels have limited ability to prevent bacterial infections such as sepsis and tetanus during wound healing and tissue regeneration. Studies demonstrated that bacterial infections could increase the level of reactive oxygen species (ROS) and lead to persistent inflammation.
To prevent bacterial infections during skin defect treatment, natural polymer-based injectable hydrogels must be endowed with antibacterial properties. NIR photothermal hydrogels can annihilate bacteria effectively without using toxic antimicrobial agents, such as quaternary ammonium salts, nanoparticles (NPs)/metal ions, and antibiotics.
Moreover, NIR photothermal hydrogels do not promote drug resistance in bacteria as their antimicrobial activities are based on the high heat locally generated by the photosensitizer under NIR laser irradiation.
Several NIR photothermal hydrogels with different photosensitizers, such as metal compounds, carbon nanomaterials, and metal NPs, were designed to replace conventional antimicrobial agent-loaded antibacterial hydrogels.
However, the high heat locally generated by the photothermal hydrogels can increase the ROS level and cause inflammation in the skin defect wound, which can delay the wound healing process.
α-lipoic acid (LA), a natural anti-oxidant with good compatibility and exceptional anti-oxidant ability, can scavenge different kinds of excess ROS in the body. LA demonstrates a significantly higher anti-oxidant activity compared to vitamin C, a common anti-oxidant.
Additionally, LA also displayed good anti-inflammatory activity against different inflammatory factors, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) by inhibiting the nuclear factor kappa-B (NF-κB) expression. Thus, the LA is typically utilized as a surfactant to modify the metal NPs to enhance their water dispersion and solubility.
Palladium NPs (PdNPs) are used extensively in photothermal therapy, including tumor treatment and sterilization, owing to their good biocompatibility and exceptional photothermal property.
However, metal NPs can easily agglomerate and precipitate in solution, which necessitates the modification of their surface during their application. LA can be used as a surfactant to modify the PdNP surface as it possesses biological functions and can improve the water solubility of the PdNPs.
In this study, researchers synthesized a novel NIR photothermal injectable hydrogel, designated as LAPdNPs/Alg hydrogel, with anti-inflammation and anti-oxidation properties by incorporating LA-modified PdNPs (LAPdNPs) into calcium ions crosslinked sodium alginate hydrogel (Alg hydrogel) for skin wound defect treatment. LA was used to modify the PdNP surface to prevent its precipitation and agglomeration.
Initially, Alg hydrogel was dissolved in a solution containing LAPdNP to obtain an Alg/ LAPdNP solution. Subsequently, 0.3 mL Alg/ LAPdNP solution and 0.05 mL 0.2 M calcium chloride solution were added to the injection tube of a double tube injection.
Eventually, both solutions were injected into various molds at the same time to obtain LAPdNPs/Alg hydrogels. Several hydrogels were prepared using a similar method by changing the LAPdNPs concentration in the Alg solution.
A scanning electron microscope (SEM) with energy dispersive X-ray spectroscopy (EDS) and rheometer was used for the characterization of the synthesized hydrogels. Researchers evaluated the NIR photothermal stability and the NIR photothermal antibacterial activity in vitro. Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were used to determine the antibacterial effect of the hydrogels in vitro with and without NIR laser irradiation.
The anti-inflammatory and anti-oxidant activities of the NIR photothermal injectable hydrogel were determined by evaluating the inflammatory factors and intracellular ROS levels, respectively. Specifically, the TNF-α and IL-1β expression was detected in 3T3 cells.
Researchers also assessed the biocompatibility, hemocompatibility in vitro, and the antibacterial effect in vivo by S. aureus-accompanied wound healing of synthesized hydrogels. A full-thickness skin defect model was utilized to assess the ability of the synthesized hydrogels to accelerate wound healing and skin regeneration.
NIR photothermal injectable LAPdNPs/Alg hydrogels were synthesized successfully. No agglomeration and precipitation were observed in the LAPdNPs even after a long duration, indicating that the LA was effectively modified on the PdNPs.
LAPdNPs/Alg solution with 100 μg/mL LAPdNPs concentration (LAPdNPs(100)/Alg solution) and calcium chloride solution was injected successfully into star-shaped, fan-shaped, and lightening-shaped to perfectly fill these irregular wound defects, which reduced the implant invasion.
Crosslinking between the carboxy group of alginate and calcium ions of calcium chloride by ionic interactions was observed. No significant change occurred in the sodium alginate structure after the incorporation of LAPdNPs.
LAPdNPs(100)/Alg hydrogel was injectable even after molding. Additionally, the hydrogel displayed good biodegradability as it disappeared completely when immersed in phosphate buffer saline for 10 days, indicating that the hydrogel could be metabolized by the body after the skin defect treatment.
The LAPdNPs(100)/Alg hydrogel possessed an interpenetrating porous structure, which was suitable for new tissue growth, cell migration, and cell proliferation.
The thermal images of LAPdNPs(100)/Alg hydrogel changed gradually from blue to red under NIR laser irradiation, with a 50 oC rise in water temperature around hydrogel observed after 10 min of irradiation compared to initial water temperature, indicating an exceptional photothermal effect.
The rise in water temperature around LAPdNPs(100)/Alg hydrogel was considerably higher compared to LAPdNPs/Alg hydrogel with 50 μg/mL LAPdNP concentration. No temperature rises or changes in thermal images were observed in Alg hydrogels.
Moreover, the LAPdNPs(100)/Alg hydrogel demonstrated excellent photothermal stability even after four cycles, which indicated the significant potential of the hydrogel for NIR photothermal sterilization to prevent bacterial infection in skin defect wounds. The NIR photothermal sterilization did not lead to drug resistance and long-term cytotoxicity.
LAPdNPs(100)/Alg hydrogel group killed over 80% of S. aureus and E. coli bacteria under NIR laser irradiation. However, no antibacterial activity was observed when Alg hydrogel was used under NIR laser irradiation due to a lack of NIR photothermal properties.
The LAPdNPs(100)/Alg hydrogel showed exceptional anti-oxidant and anti-inflammatory activities and could effectively reduce the intracellular ROS level and inflammatory factors induced by photothermal therapy and bacterial infection.
The hydrogel scavenged more than 60% of ROS in cells and reduced the relative expression level of TNF-α and IL-1β genes by 52.9% and 53.3%, respectively, accelerating skin defect wound healing and promoting the skin tissue regeneration process.
All hydrogels with different LAPdNP concentrations displayed good hemocompatibility as they did not cause blood cell aggregation and rupture of red blood cells, which indicated their potential for wound dressing.
The LAPdNPs(100)/Alg hydrogel group demonstrated a higher antibacterial activity in vivo against S. aureus under NIR laser irradiation compared to LAPdNPs(100)/Alg hydrogel group without NIR laser irradiation after 15 days of treatment.
Additionally, the LAPdNPs(100)/Alg hydrogel group with laser irradiation also displayed a faster-wound healing rate, indicating the ability of the hydrogel to prevent wound infection and accelerate bacteria-accompanied wound closure.
The skin wound defect area treated using LAPdNPs(100)/Alg hydrogel group was substantially smaller after five and 10 days of implantation, and after 15 days, new skin completely filled the wound area.
Taken together, the findings of this study demonstrated the effectiveness of NIR photothermal injectable LAPdNPs/Alg hydrogel with anti-inflammation and anti-oxidation properties in accelerating the treatment of clinical skin defects.
Li, P., Lu, R., Liu, C. et al. Scavenging ROS and inflammation produced during treatment to enhance the wound repair efficacy of photothermal injectable hydrogel. Biomaterials Advances 2022. https://doi.org/10.1016/j.bioadv.2022.213096
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