Electrospun Chitosan–Polyvinyl Alcohol Nanofiber Dressings Loaded with Bioactive Ursolic Acid Promoting Diabetic Wound Healing

Abstract

The design and development of novel dressing materials are urgently required for the treatment of chronic wounds caused by diabetic ulcers in clinics. In this study, ursolic acid (UA) extracted from Chinese herbal plants was encapsulated into electrospun nanofibers made from a blend of chitosan (CS) and polyvinyl alcohol (PVA) to generate innovative CS-PVA-UA dressings for diabetic wound treatment. The as-prepared CS-PVA-UA nanofiber mats exhibited randomly aligned fiber morphology with the mean fiber diameters in the range of 100–200 nm, possessing great morphological resemblance to the collagen fibrils which exist in the native skin extracellular matrix (ECM). In addition, the CS-PVA-UA nanofiber mats were found to possess good surface hydrophilicity and wettability, and sustained UA release behavior. The in vitro biological tests showed that the high concentration of UA could lead to slight cytotoxicity. It was also found that the CS-PVA-UA nanofiber dressings could significantly reduce the M1 phenotypic transition of macrophages that was even stimulated by lipopolysaccharide (LPS) and could effectively restore the M2 polarization of macrophages to shorten the inflammatory period. Moreover, the appropriate introduction of UA into CS-PVA nanofibers decreased the release levels of TNF-α and IL-6 inflammatory factors, and suppressed oxidative stress responses by reducing the generation of reactive oxygen species (ROS) as well. The results from mouse hepatic hemorrhage displayed that CS-PVA-UA nanofiber dressing possessed excellent hemostatic performance. The in vivo animal experiments displayed that the CS-PVA-UA nanofiber dressing could improve the closure rate, and also promote the revascularization and re-epithelization, as well as the deposition and remodeling of collagen matrix and the regeneration of hair follicles for diabetic wounds. Specifically, the mean contraction rate of diabetic wounds using CS-PVA-UA nanofiber dressing could reach 99.8% after 18 days of treatment. In summary, our present study offers a promising nanofibrous dressing candidate with multiple biological functions, including anti-inflammation, antioxidation, pro-angiogenesis, and hemostasis functions, for the treatment of hard-to-heal diabetic wounds.

Chitosan-Based Biomaterials for Tissue Regeneration

“…Moreover, it possesses anti-inflammatory properties by suppressing M1 and stimulating M2 phenotype of macrophages, inhibiting TNF-α and IL-6 expression, and reducing ROS production. The in vivo study revealed an improved closure rate and enhanced revascularization and re-epithelization [ 119 ].…”

Modulation of Macrophage Function by Bioactive Wound Dressings with an Emphasis on Extracellular Matrix-Based Scaffolds and Nanofibrous Composites

“…Because they have many desirable properties for skin wound healing, nanofibrous composites have received significant attention in the past few decades [ 97 , 98 , 99 , 100 , 101 ]. Nanofibers can be designed to possess a random or aligned structure, and the fiber diameter can be adjusted to closely match that of collagen fibrils in the natural skin ECM (i.e., the range of 100–200 nm).…”

“…The UA-loaded nanofibers significantly reduced the M1 phenotypic polarization of macrophages and effectively restored the M2 polarization in vitro. In a diabetic wound model, this scaffold was found to improve wound closure, re-epithelialization, revascularization, and hair follicle regeneration [ 99 ]. Similarly, anemoside B4, an anti-inflammatory ingredient of the Chinese medicine Pulsatilla , has been loaded into an electrospun nanofibrous wound dressing, which significantly suppressed the lipopolysaccharide-stimulated differentiation of pro-inflammatory macrophages in vitro and accelerated diabetic wound healing in vivo [ 103 ].…”

Design, development, in-vitro and in-vivo evaluation of polylactic acid-based multifunctional nanofibrous patches for efficient healing of diabetic wounds

“…Briefly, slow rate of ulcer healing leads to microbial infection, gangrene, and trauma. Infected foot ulcer usually leads to hospitalization and ends up with amputation 2 – 4 . Delayed healing in diabetic patients is attributed to complicated pathological features that retard the healing process 5 .…”

“…Although wound closure occurs naturally, it is extremely complicated in diabetic patients as there is no well-defined followed protocol till now for the complete healing of diabetic wounds and ulcers 2 , 15 .…”