# A Study on the Stoichiometry of Casein/Chitosan Gel Complexes as a Delivery System for Quercetin
## 1 Introduction  
As the biggest organ, it is important to keep the skin healthy and intact, so that it can protect the whole body from external traumas. In cases of injury or harm, especially ones damaging to its integrity in depth, the protective function of the skin as a barrier can be compromised. An appropriate treatment procedure should be applied, depending on the depth and the stage of the wound [1]. Sometimes, treatment plans can be extended up to 12 weeks. In cases where the wound is chronic, the healing process can be prolonged, and the wound spot becomes more susceptible to bacterial infections [2]. In most cases, in order to avoid the development of infections in and around the wound, the prescription of antibiotics is required, but the significant increase in the number of drug-resistant bacteriumtypes is increasingly/quite worrying [1]. A possible way out of this is to combine the existing antibiotic therapy with a biologically active compound that can prevent bacterial development. An appropriate candidate for this could be quercetin. This compound is naturally found in different fruits and vegetables and belongs to the flavanol group [3]. Along with its high antioxidant activity and biocompatibility, quercetin also shows antiviral, anti-inflammatory, anti-microbial, and even anti-carcinogenic properties [4; 5]. It is able to downregulate proteins responsible for tumorigenesis and development and it can affect cell signalling and enzyme inhibition, according to [PERSON] et al. [6]. However, its treatment potential cannot be fully exploited due to its poor solubility. One of the often-chosen and effective methods for improving the compound is to encapsulate it into hydrogel particles. As a matter of fact, gel-based particles made of biopolymers are a suitable carrier for bioactive compounds with low solubility [7], low skin permeability [8], and poor in vivo behaviour [9]. Due to their high flexibility and biocompatibility, they have become an emerging tool for encapsulation and delivery of different types of active compounds, not only in the pharmacy industry, but also in medical skin care products [10], cosmetics [11], the food industry [12], etc. In addition, the overall synergistic outcome between the active compound and the gel cargo system is quite easy to achieve [13]. Gel particles are suitable for enhancing quercetin solubility and its delivery onto a desired spot on the skin. [PERSON] et al. have concluded that quercetin encapsulated into PVA-alginate hydrogels shows appropriate penetration in ex vivo skin models [14]. Hydrogels developed by [PERSON] et al. [1] demonstrate proper mechanical resilience and water vapour transmission rate, along with a synergetic effect between the active compound and the matrix consisting of quatermized chitosan and polyacrylamide. Besides its anti-microbial activities, chitosan also possesses other valuable features, such as mucoadhesion, biocompatibility, degradability, and lack of toxicity [15; 16]. Along with this, chitosan hydrogels also show hemostatic, wound healing effects and anti-inflammatory actions [17]. Being a weak polyelectrolyte, when placed in conditions up to its pKa of \(\sim\)6.5, at least 50% of the macromolecules of chitosan/macromolecules present in chitosan are positively charged. Thus, based on electrostatic interactions, it can form a variety of structures (hydrogel particles [18], thin films [19], multi-layered films [20], etc.) suitable for delivering active compounds for skin treatment. Casein is a weak polyelectrolyte and protein with an isoelectric point at pH = 4.6. At higher pH levels, it is negatively charged [21]. Casein can form micelles in water conditions above its critical micellar concentration, and it possesses film-forming, gelling, and foaming properties. It is proven to be safe for biomedical applications due to its biocompatibility and biodegradability [22; 23]. Also, it has both hydrophobic and hydrophilic domains and can interact with various compounds [24].