## 4 Polyphenol-Based Systems and Their Unveiling Potential for Wound Care
### Natural versus Synthetic Polymers for Polyphenol Carrier Design
Chitosan is one of the most used polymers as coating materials due to its cationic character based on its primary amino groups, which gives it extraordinary properties, such as controlled drug release, in situ gelation, and mucoadhesion [107]. Moreover, chitosan is also characterized by its excellent hemostasis capability and antimicrobial, antifungal, and antiulcer properties [107]. This non-toxic and biocompatible polymer is considered a safe material by the United States Food and Drug Administration (FDA), and it is one of the most used biopolymers both in pharmaceutical and biomedical applications, including the wound healing area and tissue engineering [107,108]. Chitosan-based hydrogels were shown to influence all four stages of wound healing by regulating the migration of neutrophils and macrophages, suppressing the infiltration of inflammatory cells, improving the inflammatory function of leukocytes, and accelerating fibroblast proliferation [109, 110, 111]. Although commercial chitosan-based hydrogels using microparticles were found, commercial chitosan-based wound dressings for chronic wounds are already available, such as Tegasorb(r) (3M Science Applied to Life, USA) and Chitoflex(r) (HemCon Medical Technologies, Portland, OR, USA) [110]. Different drugs, such as growth factors, antimicrobial agents, hormones, antifungal, and stem cells can be incorporated into chitosan microparticles in order to improve the efficacy of their properties [110,112]. Chitosan microparticles have also offered great promise in topical applications, and recently, this polymer has been studied as an encapsulating material for polyphenols [81]. Curcumin was encapsulated into chitosan/poly-y-glutamic/pluronic nanoparticles by [PERSON] et al. for the local treatment of wounds. The authors proved the encapsulation of the polyphenol ensured a controlled release in phosphate buffer solution, simulating the wound exudate [113]. On the other hand, hyaluronic acid is a biocompatible, biodegradable, and non-toxic hydrophilic polymer. As chitosan, hyaluronic acid has also been used in tissue engineering and wound care due to its antimicrobial, antioxidant, and anti-inflammatory activities. Moreover, hyaluronic acid is known to bind to the components of the extracellular matrix that undergoes remodeling during regeneration [114]. However, when applied to the wound, hyaluronic acid has the disadvantage of reduced wound breathability [115]. In order to overcome this drawback, a hydrogel composed of hyaluronic acid and poloxamer was developed and studied, revealing excellent results in terms of air permeability, promoting skin-wound healing and increasing protein accumulation, and isolating skin wounds from bacterial invasion [116]. The use and effectiveness of hyaluronic acid as a coating material of micro- and nanoparticles in wound care was already studied and proved [117, 118, 119]. As an example, [PERSON] et al. developed microparticles of hyaluronic acid with epidermal growth factor by emulsion for the purpose of targeted and sustained epidermal growth factor delivery to damaged extracellular matrix in acute wounds [117]. Studies of polyphenols-loaded hyaluronic micro or nanoparticles were not founded. However, wound healing efficacy of curcumin conjugated to hyaluronic acid was studied, exhibiting higher values of antimicrobial and antioxidant activity and migration of cells in scratch wounds compared to treatment with native curcumin [120]. These results suggest that hyaluronic acid conjugation with curcumin is a promising formulation for enhancing its healing efficacy.