Wound care has attracted a lot of attention in recent years due to the increased incidence and the burden of injuries [1]. To achieve suitable wound care and faster recovery of the same, the selection of an appropriate wound dressing is crucial. The majority of available wound dressing, fails to provide the desired active and moist environment required for wound healing. In addition, there are chances that the wound dressings may stick to the wound area and cause pain to the patients, making it uncomfortable [2]. They have short residence time with less efficacy and more chances of infections. Ideally, a wound dressing should provide a moist environment and prevent the wounds from drying. It should be permeable to oxygen, comfortable, and reduce necrosis of the wound surface [3]. Further, the dressing material should be biocompatible, biodegradable and non-toxic. Hence, designing and fabricating newer and advanced wound dressing materials with several functions is the need of the hour to lower the burden of wound care on the healthcare system and overcome the challenges associated with the currently available wound dressings.

Electrospinning is a versatile and highly explored technology to fabricate uniform and nanofibrous wound dressings with controlled porosity and average diameters ranging from a few μm to nm using different natural and synthetic polymers [4,5]. The interesting advantage of electrospinning technology is that the diameters of the fabricated nanofibrous membrane are of the same size range as that of the collagen fibrils in the skin tissues [6]. Studies have demonstrated the effectiveness of the electrospun nanofibrous sheet in promoting cell adherence, in-vitro proliferation of cells and in vivo angiogenesis, promoting faster wound healing and tissue regeneration [7]. The unique advantage of electrospinning-based nanofibers is their nonwoven mat-like structure which makes it a potential candidate for wound dressing due to its in-built property to provide air and moisture permeability along with pathogen barrier properties [8]. Numerous natural and synthesized polymers are explored to fabricate nanofibrous wound dressing via the electrospinning technique.

Chitosan (CS)-based biomaterials exhibit excellent properties, including good biocompatibility, non-toxicity, widespread availability, low cost, biodegradability, antibacterial, anti-inflammatory, and hemostatic properties, which makes it an ideal choice for formulating wound dressings [9]. Despite several advantages offered by CS, its limited water solubility lowers its interaction with the wound site, wound fluids, and blood, which slows down its healing ability [10]. Additionally, due to the absence of H-atom donors, CS lacks antioxidant properties, which have a major role to play in wound healing. Hence grafting polyphenols on the backbone of CS would be a better alternative to overcome these shortcomings and enhance its solubility and antioxidant properties.

Polyphenols are the secondary metabolites present in plants and act as natural antioxidants [11]. Studies have indicated that reactive oxygen species (ROS) are the oxidizing agents that have a crucial role to play during the normal wound healing response. A proper balance between high and low levels of ROS is required through the use of antioxidants to exert a protective effect against the infected tissue and promote wound healing [12]. Gallic acid (GA), also known as 3, 4, 5- trihydroxy benzoic acid, is a bioactive phenolic compound occurring in the kingdom of plantae and is known to have various pharmacological activities such as antioxidant, antimicrobial, and anti-inflammatory. GA stimulates the genes responsible for antioxidant activity. Further, ameliorates the fibroblasts and keratinocytes migration and hence plays a pivotal role in wound healing [12]. The unique advantages of GA in terms of its availability, low toxicity, cost, and multiple pharmacological effects make it a choice compared to expensive growth factors incorporated in the wound dressings.

To optimize the benefits of CS and GA, a free radical-based polymerization reaction was used to synthesize gallic acid-chitosan conjugate (GAC). Unfortunately, the mechanical properties and electro spinnability of synthesized GAC conjugate was less. One of the approaches to improve the spinnability of CS-based matrix is to blend it with polymers such as Polyacaprolactone (PCL) to fabricate electrospun-based nanofibers with improved mechanical properties, cell adherence, and ease of processability [13]. PCL is a widely explored polymer for wound healing. It is FDA-approved, biocompatible, and biodegradable polymer with the ability to decrease inflammatory infiltration [14].

This work is the first of its kind in which the GAC conjugate is electrospun to form a nanofibrous wound dressing, wherein the characteristics of GA and CS work synergistically with the biodegradability of PCL to form a biomaterial-based wound dressing to enhance the wound healing process. The conjugate of CS with GA was formed using the free radical polymerization method. Many researchers have incorporated this technique to form the conjugate of GAC, but to date electrospinning such a conjugate into a nanofiber mat is not reported to design wound dressing nanofiber mats. Electrospun nanofiber mats containing plant extract such as Garcinia mangostana is reported to accelerate wound healing using chitosan-ethylenediaminetetraacetic acid/polyvinyl alcohol as polymer. The mats exhibited anti-oxidant and anti-bacterial properties and were biodegradable and biocompatible [15]. Marzano et al. reported the development of three-dimensional CS-based complexes loaded with GA by the process of simple adsorption. The authors discovered that the CS-based complexes retained anti-oxidant and antibacterial properties [16].

In the present work, GAC conjugates were prepared by a safe free radical induced grafting approach and characterized by X-ray diffraction, FTIR, UV visible spectroscopy, and differential scanning calorimetry. The synthesized GAC conjugates were evaluated for antioxidant assay and further, the conjugates were converted into nanofibrous dressings via electrospinning using PCL. The GAC/PCL nanofibrous dressings were evaluated for morphology, angle of contact, in vitro drug release, and thermal properties. The chick yolk sac membrane (YSM) assay was used to evaluate the angiogenesis potential of the nanofibrous dressings. The biocompatibility and the cytotoxicity of GAC-PCL nanofibrous dressings were evaluated by in vitro cell culture assays. Importantly, the wound-healing potential of the nanofibrous dressings was investigated by developing an excision wound model in rats. The study demonstrated the fabrication of novel GAC conjugate electrospun PCL nanofibers to exert a promising role in wound recovery and tissue regeneration.