# Development of a Natural Matrix Hybrid Hydrogel Patch and Evaluation of Its Efficacy against
## 1 Introduction  
In cases of atopic dermatitis (AD), genetic and acquired factors damage the skin barrier but the cause of AD is unknown [1]. AD is classified into infant, pediatric, and adult types according to onset age. Furthermore, acute, subacute, and chronic AD exhibit different symptoms as well as varying lesion types and distribution. AD is a representative disease of childhood and adolescence that is most often observed in infants and children and can develop into a chronic, recurrent, inflammatory skin disease. Symptoms begin around 100 days after birth in infants. Dry skin, erythema (skin redness), and scales (white debris) improve and worsen in a cycle that results in a malfunction of the barrier formed by the skin. This allows harmful external substances to easily penetrate the skin; these allergic irritants that invade the skin cause AD [2, 3]. Currently, there is no cure for AD. However, several researchers have suggested basic methods to protect the skin and identify and remove inducers of AD, as well as treatments to supply moisture to the skin and reduce itchiness. Topical steroids and local calcineurin inhibitors are the most commonly used drug treatments. Although topical steroids have a strong effect, the use of steroid ointments and creams leads to excessive immune response suppression that can result in pathogen propagation that may exacerbate skin infections [4]. Furthermore, steroid ointments inhibit collagen synthesis; overuse may decrease the collagen layer of the skin and result in atrophy and thinner skin [5]. Continued skin blood vessel dilation (in which the skin turns red and blood vessels are visible to the naked eye) may lead to side effects such as vasodilation, skin irritation, rashes, and swelling [6]. The lack of therapeutic drug treatments for AD has resulted in the exploration of natural resources to alleviate AD symptoms and minimize side effects, even when used for extended periods. Several studies have reported that AD symptoms improve after using various medicinal materials including herbal, headworm, and _Opuntia humifusa_ extracts [7; 8]. _Centella asatica_ extract (CAE) effectively promotes wound regeneration and eliminates the appearance of acne scars by reducing pigmentation. Moreover, it promotes cell proliferation, collagen synthesis, and fibronectin production, which helps to increase pore elasticity and shrink pores [9]. Other studies have shown that it is effective in preventing fine wrinkles and treating eczema, as well as relieving the itching and repairing the damaged skin associated with AD [10; 11]. However, an appropriate concentration of CAE must be used as excessive CAE may lead to hypertrophic scarring that remains when recovering from keloid inflammation. Despite this, innovative treatments for AD are still lacking. Since AD is sensitive to skin irritation, the development of patches that can effectively adhere to and be absorbed in a localized area to release therapeutic treatments with minimal skin irritation should be a priority [12; 13]. The materials and manufacturing methods used to form hydrogels must be carefully chosen to meet specific criteria such as binding affinity, biomaterial toxicity, and biocompatibility. Furthermore, materials with an extracellular matrix are essential for tissue regeneration. Dextran (Dex) [14] and hyaluronic acid (HA) [15; 16] are widely used as drug delivery materials. HA is generally water soluble; however, HA must be insoluble in aqueous solutions for cells to attach to it. Therefore, HA must be chemically modified to enable its use as a cell scaffold despite its excellent biocompatibility and ability to promote angiogenesis [16]. To solve these problems, this study aimed to develop a new hydrogel formulation that can effectively control the release of therapeutic agents to specific local areas with minimal skin irritation. HA and Dex were mixed with a crosslinking agent, 1,4-butanediol diglycidyl ether (BDDE), to develop HA-Dex hybrid hydrogel patches.